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Pobbati, Ajaybabu V., and Brian P. Rubin. "Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional Complex." Molecules 25, no. 24 (December 18, 2020): 6001. http://dx.doi.org/10.3390/molecules25246001.
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The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The transcriptional co-regulator YAP (its homolog TAZ) interact with the surface pockets of TEADs. Peptidomimetic modalities like cystine-dense peptides and YAP cyclic and linear peptides exploit surface pockets (interface 2 and interface 3) on TEADs and function as PPIDs. The TEAD surface might pose a challenge for generating an effective small molecule PPID. Interestingly, TEADs also have a central pocket that is distinct from the surface pockets, and which small molecules leverage exclusively to disrupt the YAP/TAZ-TEAD interaction (allosteric PPIDs). Although small molecules that occupy the central pocket belong to diverse classes, they display certain common features. They are flexible, which allows them to adopt a palmitate-like conformation, and they have a predominant hydrophobic portion that contacts several hydrophobic residues and a small hydrophilic portion that faces the central pocket opening. Despite such progress, more selective PPIDs that also display favorable pharmacokinetic properties and show tolerable toxicity profiles are required to evaluate the feasibility of using these PPIDs for cancer therapy.
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Kim, Jisook, Seung Hyun Jung, Seon Yeong Han, Jihee Yoon, Minjeong Kim, Jooyun Byun, Heesun Moon, et al. "Abstract 1614: Antitumor activity of novel and potent YAP/TAZ-TEAD inhibitorstargeting the Hippo pathway in solid tumors." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1614. http://dx.doi.org/10.1158/1538-7445.am2023-1614.
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Abstract The Hippo pathway is evolutionarily conserved and known to regulate diverse cellular processes, including cell survival, proliferation, differentiation, migration, and organ size. The key regulator of Hippo pathway is transcriptional enhanced associate domain (TEAD) transcription factors, which directly bind with YAP/TAZ and then drive the multiple signaling by activating target gene expression on nuclear. Loss-of-function mutations in the upstream activators, NF2-LATS1/2-MST1/2, trigger YAP/TAZ nuclear translocation and target gene transcription (Hippo-off state). This YAP/TAZ-TEAD complex is overexpressed and leads to metastatic progression in various cancers including malignant mesothelioma, NSCLC, ovarian cancer or cholangiocarcinoma. A recent development in targeting the Hippo pathway has been focused on the discovery of a central lipophilic pocket in TEAD amenable to the small-molecule binding site of autopalmitoylation. Within this lipophilic palmitate pocket, post-translational S-palmitoylation of TEAD at a conserved catalytic cysteine (Cys) residue (e.g., C380) leads to TEAD stabilization and is believed to be critical for maintaining appropriate protein folding to enable the formation of the transcriptionally active YAP/TAZ -TEAD complex. Therefore, targeting the palmitate pocket with allosteric small molecules inhibitor disrupt the formation of the YAP/TAZ-TEAD complex and modulate YAP/TAZ-TEAD driven gene transcription. We have identified a series of novel, potent small-molecule inhibitors of the YAP/TAZ-TEAD transcriptional complex. It showed under 20 nM of potency in the inhibition of TEAD luciferase reporter assay in MCF7-TEAD-luc cells. These TEAD inhibitors inhibited YAP/TAZ-TEAD protein-protein interaction in H226 cells harboring neurofibromin 2 (NF2) alteration. In addition, our lead compounds exhibited dose-dependent growth inhibitory effects in Hippo pathway-altered cancer cell lines and reduced the YAP/TAZ-TEAD target gene expression, CTGF, and CYR61 in H226 cells. Our lead compounds, singled out and optimized based on in vitro functional assay, displayed favorable pharmacokinetic and safety profiles. Furthermore, orally administered lead compound effectively suppressed tumor growth within tolerable doses in xenograft mice with tumors harboring NF2 alteration as a major upstream molecule of the Hippo pathway. In summary, we pointed our novel YAP/TAZ-TEAD inhibitors that showed excellent efficacy in Hippo-altered mutant cancer in vitro and in vivo xenograft models. These data best support a therapeutic option for the treatment of cancers with amplified or overexpressed YAP, TAZ, or TEAD genes. Further preclinical studies will be performed and reported soon after the establishment of a preclinical candidate. Citation Format: Jisook Kim, Seung Hyun Jung, Seon Yeong Han, Jihee Yoon, Minjeong Kim, Jooyun Byun, Heesun Moon, Eunyoung Lee, Yu-Yon Kim, Hyunjin Park, So-Ye Jeon, Young Gil Ahn, Young Hoon Kim, Kwee Hyun Suh. Antitumor activity of novel and potent YAP/TAZ-TEAD inhibitorstargeting the Hippo pathway in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1614.
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Moure, Casey J., Christopher Sondey, Mangeng Cheng, My Mansueto, Rafael Fernandez, Sebastian E. Schneider, Julia V. Ramirez, et al. "Abstract 3938: Discovery of a novel small molecule inhibitor of the YAP1/TAZ-TEAD transcriptional complex." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3938. http://dx.doi.org/10.1158/1538-7445.am2022-3938.
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Abstract Hippo pathway alterations in human cancers often result in dephosphorylation of yes-associated protein (YAP1) and its paralog TAZ (WWTR1), allowing the formation of an active complex with transcriptional enhanced associate domain transcription factors (TEADs). This complex formation results in the activation of pro-survival and pro-proliferative transcriptional programs in cancer cells. Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of tumors are driven by YAP1/TEAD activity. Although traditionally difficult to drug with small molecules, identification of autopalmitoylation sites in the hydrophobic palmitate pocket of TEADs necessary for YAP1 interaction has enabled modern drug discovery platforms to generate compounds that allosterically inhibit YAP1/TAZ-TEAD complex formation and transcriptional activity. We report the discovery and characterization of the novel YAP1/TAZ-TEAD inhibitor MRK-A from an aryl ether chemical series demonstrating potent and specific inhibition of YAP1/TAZ-TEAD activity. In biochemical thermal shift assays, MRK-A caused a concentration-dependent melting temperature shift of 8-12.5 and 0.6-1.5 degrees for TEAD1 and TEAD2, respectively, indicating direct binding to TEAD protein. In cellular assays, MRK-A demonstrated inhibition of a TEAD-based reporter assay, with little to no activity in multiple orthogonal off-target reporter assays such as WNT, NF-KB, TGFB and PPARG (8.4 nM vs. >10000 nM), which is consistent with the exquisite selectivity profile of this molecule (>1000x selectivity against 350+ measured kinases and other common off-targets). In the NF2-deficient mesothelioma cell line H226, MRK-A suppressed the transcription of endogenous YAP/TAZ-TEAD target genes CYR61, ERBB3, ANKRD1 and CTGF (50-75% inhibition at 100 nM), but not LATS1, a non-TEAD regulated Hippo pathway gene. In co-immunoprecipitation assays, MRK-A disrupted the interaction of YAP1 and TEAD in H226 cells at concentrations consistent with inhibition of target genes. In addition, MRK-A potently blocked the clonogenic growth and viability of H226 cells in a dose-dependent manner (maximal response at 1 µM compound >90% growth inhibition), while sparing the Hippo wild-type mesothelioma cell line H28. Furthermore, structurally similar control compounds, MRK-B and MRK-C, without the ability to block TEAD-mediated transcription (TEAD reporter MCF7 assay IC50 > 10000 nM), did not impact the clonogenic growth of H226 cells. In vivo, MRK-A did not show acute tolerability signals in mice and demonstrated pharmacokinetics suitable for daily oral dosing in efficacy studies. In summary, we report the structure and characterization of MRK-A demonstrating potent and specific inhibition of YAP1/TAZ-TEAD mediated transcriptional responses, with potential implications for treating malignancies driven by altered Hippo signaling. Citation Format: Casey J. Moure, Christopher Sondey, Mangeng Cheng, My Mansueto, Rafael Fernandez, Sebastian E. Schneider, Julia V. Ramirez, Brian Long, Erin DiMauro, Brandon Vara, Charles Yeung, Abe Achab, Jongwon Lim, Ronald Kim, Cayetana Zarate, Jonathan Bennett, Rachel Palte, Robert Foti, Vladimir Simov, Evan Barry. Discovery of a novel small molecule inhibitor of the YAP1/TAZ-TEAD transcriptional complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3938.
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Li, Z., B. Zhao, P. Wang, F. Chen, Z. Dong, H. Yang, K. L. Guan, and Y. Xu. "Structural insights into the YAP and TEAD complex." Genes & Development 24, no. 3 (February 1, 2010): 235–40. http://dx.doi.org/10.1101/gad.1865810.
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Lauriola, Angela, Elisa Uliassi, Matteo Santucci, Maria Laura Bolognesi, Marco Mor, Laura Scalvini, Gian Marco Elisi, et al. "Identification of a Quinone Derivative as a YAP/TEAD Activity Modulator from a Repurposing Library." Pharmaceutics 14, no. 2 (February 10, 2022): 391. http://dx.doi.org/10.3390/pharmaceutics14020391.
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The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are the major downstream effectors in the Hippo pathway and are involved in cancer progression through modulation of the activity of TEAD (transcriptional enhanced associate domain) transcription factors. To exploit the advantages of drug repurposing in the search of new drugs, we developed a similar approach for the identification of new hits interfering with TEAD target gene expression. In our study, a 27-member in-house library was assembled, characterized, and screened for its cancer cell growth inhibition effect. In a secondary luciferase-based assay, only seven compounds confirmed their specific involvement in TEAD activity. IA5 bearing a p-quinoid structure reduced the cytoplasmic level of phosphorylated YAP and the YAP–TEAD complex transcriptional activity and reduced cancer cell growth. IA5 is a promising hit compound for TEAD activity modulator development.
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Sheldon, Caroline, Aaron Farley, Qing Ma, William T. Pu, and Zhiqiang Lin. "Depletion of VGLL4 Causes Perinatal Lethality without Affecting Myocardial Development." Cells 11, no. 18 (September 10, 2022): 2832. http://dx.doi.org/10.3390/cells11182832.
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Congenital heart disease is one of the leading causes of pediatric morbidity and mortality, thus highlighting the importance of deciphering the molecular mechanisms that control heart development. As the terminal transcriptional effectors of the Hippo–YAP pathway, YAP and TEAD1 form a transcriptional complex that regulates the target gene expression and depletes either of these two genes in cardiomyocytes, thus resulting in cardiac hypoplasia. Vestigial-like 4 (VGLL4) is a transcriptional co-factor that interacts with TEAD and suppresses the YAP/TEAD complex by competing against YAP for TEAD binding. To understand the VGLL4 function in the heart, we generated two VGLL4 loss-of-function mouse lines: a germline Vgll4 depletion allele and a cardiomyocyte-specific Vgll4 depletion allele. The whole-body deletion of Vgll4 caused defective embryo development and perinatal lethality. The analysis of the embryos at day 16.5 revealed that Vgll4 knockout embryos had reduced body size, malformed tricuspid valves, and normal myocardium. Few whole-body Vgll4 knockout pups could survive up to 10 days, and none of them showed body weight gain. In contrast to the whole-body Vgll4 knockout mutants, cardiomyocyte-specific Vgll4 knockout mice had no noticeable heart growth defects and had normal heart function. In summary, our data suggest that VGLL4 is required for embryo development but dispensable for myocardial growth.
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Kim, Eui Hyun, and Seok-Gu Kang. "CSIG-25. DIFFERENTIAL YAP ACTIVITY IN HUMAN GLIOBLASTOMA TUMORSPHERES AS A POTENTIAL BIOMARKER." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii44. http://dx.doi.org/10.1093/neuonc/noac209.174.
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Abstract BACKGROUND Hippo/YAP signaling pathway has emerged as an important driver of GBM. However, the clinical significance and expression correlation of YAP in GBM is still unknown. The purpose of this study is to elucidate the regulatory functions of YAP in response to tumorspheres (TS) in GBM. Material and METHODS In GBM-tumorspheres (TS), mRNA levels of Yap1 and TAZ were determined by RNA-Seq, and nuclear YAP1 expression level and its correlation with tumor aggressiveness were assessed through nucleus cytosolic fractionation, quantitative confocal microscopy, western blot, and TEAD4 reporter assay. Cell proliferation, stemness, and invasive properties were also measured using YAP siRNA and its inhibitor Verteporfin to reveal the effect of YAP on glioma progression. In orthotopic xenograft models, the inhibition of YAP function were tested. RESULTS All GBM-TS exhibited various phosphorylation states of YAP but no significant differences regarding the expression of YAP. Among them, TS15-88 cell line showed relatively low YAP phosphorylation in the quantified immunoblot results. Indeed, TS with reduced YAP phosphorylation was associated with aggressive cancer phenotypes. Predominant nuclear localization of YAP and binding of YAP/TAZ to TEAD in the nucleus was evident in the TS15-88 cells. The YAP knockdown (KD) by siRNA significantly resulted decrease in TS proliferation through WST and ATP assay and values were validated again through YAP inhibitor, Verteporfin (VP). YAP KD attenuated not only the invasion and stemness of TS but also caused a reduction in tumor volume and prolonged the overall survival of mice. CONCLUSION We showed alteration of gene activities by YAP and nuclear localization of YAP/TAZ complex contributes to GBM progression. Moreover, thus tuning of Yap activity results a marked suppression in aggressive phenotypes of cancer. These associations emphasize that the YAP signaling network highly suggests new therapeutic opportunities in diagnosing and treating GBM.
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Kim, Cho-Long, Yu-Su Shin, Sue-Hee Choi, Seroc Oh, Kyeongseob Kim, Han-Sol Jeong, and Jung-Soon Mo. "Extracts of Perilla frutescens var. Acuta (Odash.) Kudo Leaves Have Antitumor Effects on Breast Cancer Cells by Suppressing YAP Activity." Evidence-Based Complementary and Alternative Medicine 2021 (February 15, 2021): 1–13. http://dx.doi.org/10.1155/2021/5619761.
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Yes-associated protein (YAP)/WW domain-containing transcription factor (TAZ) is critical for cell proliferation, survival, and self-renewal. It has been shown to play a crucial oncogenic role in many different types of tumors. In this study, we investigated the antitumor effect of the extracts of Perilla frutescens var. acuta (Odash.) Kudo leaves (PLE) on Hippo-YAP/TAZ signaling. PLE induced the phosphorylation of YAP/TAZ, thereby inhibiting their activity. In addition, the treatment suppresses YAP/TAZ transcriptional activity via the dissociation of the YAP/TAZ-TEAD complex. To elucidate the molecular mechanism of PLE in the regulation of YAP activity, we treated WT and cell lines with gene knockout (KO) for Hippo pathway components with PLE. The inhibitory effects of PLE on YAP-TEAD target genes were significantly attenuated in LATS1/2 KO cells. Moreover, we found the antitumor effect of PLE on MDA-MB-231 and BT549, both of which are triple-negative breast cancer (TNBC) cell lines. PLE reduced the viability of TNBC cells in a dose-dependent manner and induced cell apoptosis. Further, PLE inhibited the migration ability in MDA-MB-231 cells. This ability was weakened in YAP and TEAD-activated clones suggesting that the inhibition of migration by PLE is mainly achieved by regulating YAP activity. Taken together, the results of this study indicate that PLE suppressed cell growth and increased the apoptosis of breast cancer (BC) cells via inactivation of YAP activity in a LATS1/2-dependent manner.
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de Andrade, Leonardo Guedes, Valério Marques Portela, Esdras Corrêa Dos Santos, Karine de Vargas Aires, Rogério Ferreira, Daniele Missio, Zigomar da Silva, et al. "FSH Regulates YAP-TEAD Transcriptional Activity in Bovine Granulosa Cells to Allow the Future Dominant Follicle to Exert Its Augmented Estrogenic Capacity." International Journal of Molecular Sciences 23, no. 22 (November 16, 2022): 14160. http://dx.doi.org/10.3390/ijms232214160.
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The molecular mechanisms that drive the granulosa cells’ (GC) differentiation into a more estrogenic phenotype during follicular divergence and establishment of follicle dominance have not been completely elucidated. The main Hippo signaling effector, YAP, has, however, emerged as a potential key player to explain such complex processes. Studies using rat and bovine GC demonstrate that, in conditions where the expression of the classic YAP-TEAD target gene tissue growth factor (CTGF) is augmented, CYP19A1 expression and activity and, consequently, estradiol (E2) secretion are reduced. These findings led us to hypothesize that, during ovarian follicular divergence in cattle, FSH downregulates YAP-TEAD-dependent transcriptional activity in GC to allow the future dominant follicle to exert its augmented estrogenic capacity. To address this, we performed a series of experiments employing distinct bovine models. Our in vitro and ex vivo experiments indicated that indeed FSH downregulates, in a concentration-dependent manner, mRNA levels not only for CTGF but also for the other classic YAP-TEAD transcriptional target genes ANKRD1 and CYR61 by a mechanism that involves increased YAP phosphorylation. To better elucidate the functional importance of such FSH-induced YAP activity regulation, we then cultured GC in the presence of verteporfin (VP) or peptide 17 (P17), two pharmacological inhibitors known to interfere with YAP binding to TEADs. The results showed that both VP and P17 increased CYP19A1 basal mRNA levels in a concentration-dependent manner. Most interestingly, by using GC samples obtained in vivo from dominant vs. subordinate follicles, we found that mRNA levels for CTGF, CYR61, and ANKRD1 are higher in subordinate follicles following the follicular divergence. Taken together, our novel results demonstrate that YAP transcriptional activity is regulated in bovine granulosa cells to allow the increased estrogenic capacity of the selected dominant follicle.
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Cheng, Wen-Chih, Osnat Bohana-Kashtan, Sebastien Morisot, Nailing Zhang, Qian Chen, Duojia Pan, and Curt I. Civin. "The YAP Transcriptional Co-Activator Is Not Required for Mouse Hematopoiesis, at Steady State or After 5FU Treatment." Blood 116, no. 21 (November 19, 2010): 1592. http://dx.doi.org/10.1182/blood.v116.21.1592.1592.
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Abstract Abstract 1592 The Yes-associated protein (YAP) is a transcriptional co-activator that interacts with many transcription factors, including RUNX2, p73, ERBB4, PEBP2α, p53BP2, SMAD7 and the TEAD/TEF proteins. Recently, it has been established that YAP is the major downstream molecule of the evolutionarily conserved Hippo signaling pathway. First elucidated in Drosophila, the Hippo signaling pathway controls organ size by regulating apoptosis and proliferation. Beginning a kinase cascade, the MST1/MST2 kinases (fly ortholog: Hippo) cooperate with the WW domain-containing SAV1 (fly ortholog: Salvador) to phosphorylate and activate the LATS1/LATS2 kinases (fly ortholog: Warts). In turn, activated LATS1/LATS2 phosphorylate and inactivate YAP (fly ortholog: Yorkie). Inactivated YAP binds to 14-3-3 and is kept in the cytosol. In contrast, unphosphorylated YAP binds to TEAD family transcription factors (fly ortholog: Scalloped) and the complex transactivates genes including cell cycle regulators (e.g. cyclin) and cell death inhibitors (e.g. IAPs, inhibitor of apoptosis). Therefore, inactivation of MST or LATS kinase, or overexpression of YAP results in organ/tissue overgrowth characterized by excessive cell proliferation and diminished apoptosis in both fly and mammals. In two transgenic mouse models, overexpression of YAP1 in liver results in reversible increase in liver size due to increased proliferation and decreased cell death of hepatocytes. Several pieces of evidence suggest that YAP regulates stem cell self-renewal and differentiation. First, transcriptional profiling of mouse stem cells (hematopoietic, neuronal and embryonic) identified both YAP1 and TEAD2 as 2 of the only 14 transcription factors commonly expressed in all 3 types of stem cell. Second, in many adult human tissues (e.g. intestine, lung, pancreas), YAP1 is preferentially expressed in stem-progenitor cell compartments. Third, in mouse intestine and chick neural tubes, overexpression of YAP results in expansion of intestinal or neural stem-progenitor cells, as well as inhibition of progenitor cell differentiation in vivo. Finally, it has been shown that YAP expression decreases during mouse ES cell differentiation. Ectopic expression of YAP can maintain ES cell pluripotency and prevent differentiation both in vitro and in vivo. Given that YAP has a proven role in regulating stem-progenitor cells in multiple tissue and multiple organisms, we set out to investigate whether YAP also regulate hematopoetic stem-progenitors in mouse and human. In conditional YAP knockout mice with a specific deletion of YAP expression in the hematopoetic system, we found no abnormalities at steady state in hemtaopoietic lineages, as assessed by CBC (complete blood counts) or immunophenotypic analysis. In addition, the YAP-null hematopietic stem-progenitors (HSPCs) had no change in vitro hematopoietic colony-forming cells. Furthermore, 5-fluorouracil treatment did not reveal a significant difference in blood cell numbers or types, between wild type and YAP-null mice. Although these results in mice suggest that YAP appears not to be required in hematopoiesis, overexpression of YAP, which promotes stem-progenitor cell proliferation in other tissues, may still provide an excellent opportunity to drive HSPC expansion. Disclosures: No relevant conflicts of interest to declare.
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Shen, Hongling, Xiaofeng Xu, Hongfei Rong, Xizhen Song, Jinheng Gao, Jie Chen, Di Zhu, et al. "Abstract 501: Discovery of BPI-460372, a potent and selective inhibitor of TEAD for the treatment of solid tumors harboring Hippo pathway aberrations." Cancer Research 83, no. 7_Supplement (April 4, 2023): 501. http://dx.doi.org/10.1158/1538-7445.am2023-501.
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Abstract The Hippo signaling pathway is critical for the regulation of organ development, tissue homeostasis, and tumorigenesis by controlling the activation status of yes-associated protein (YAP) or its homolog PDZ-binding motif (TAZ). As a major downstream effector, the transcription factor TEAD is activated by forming a complex with YAP/TAZ. Hippo pathway aberrations, such as NF2-deficiency or LATS1/2 mutations leading to hyperactivation of YAP/TAZ and subsequent activation of TEAD, have been reported in many cancers, including mesothelioma, meningioma, soft tissue sarcoma and non-small cell lung cancer. Inhibiting TEAD auto-palmitoylation by directly blocking the palmitoylation pocket of TEAD is a potential therapeutic approach for cancer treatment. Here we present BPI-460372, a novel small molecule that directly blocks the TEAD auto-palmitoylation. BPI-460372 covalently and irreversibly binds to the cysteine residue in the TEAD palmitoylation pocket, preventing TEAD palmitoylation and inhibiting its biological function. BPI-460372 significantly inhibits the expression of a TEAD-responsive element reporter, as well as the mRNA of downstream target genes such as CTGF and CYR61 in NF2-deficient cells. At the cellular level, BPI-460372 strongly inhibited the proliferation of tumor cells harboring Hippo pathway aberrations. BPI-460372 also significantly suppressed tumor growth in NF2-deficient or LATS1/2 mutation xenograft models. In addition, BPI-460372 exhibited excellent oral bioavailability, high exposure across multiple species, and adequate ADME properties. In conclusion, BPI-460372 is a potent and selective TEAD palmitoylation inhibitor for the treatment of solid tumors harboring Hippo pathway aberrations. It is planned to enter Phase I clinical trial in China in early 2023. Citation Format: Hongling Shen, Xiaofeng Xu, Hongfei Rong, Xizhen Song, Jinheng Gao, Jie Chen, Di Zhu, Xiangdong Zhao, Jun Tong, Zhengyao Zou, Xiaoyun Liu, Jin Guo, Yan Xu, Yabin Li, Xiangyong Liu, Hong Chen, Jiayu Zhao, Yanju Liu, Xuepeng Ju, Haibo Chen, Hong Lan, Lieming Ding, Jiabing Wang. Discovery of BPI-460372, a potent and selective inhibitor of TEAD for the treatment of solid tumors harboring Hippo pathway aberrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 501.
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Gnedeva, Ksenia, Xizi Wang, Melissa M. McGovern, Matthew Barton, Litao Tao, Talon Trecek, Tanner O. Monroe, et al. "Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal." Proceedings of the National Academy of Sciences 117, no. 24 (June 1, 2020): 13552–61. http://dx.doi.org/10.1073/pnas.2000175117.
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Precise control of organ growth and patterning is executed through a balanced regulation of progenitor self-renewal and differentiation. In the auditory sensory epithelium—the organ of Corti—progenitor cells exit the cell cycle in a coordinated wave between E12.5 and E14.5 before the initiation of sensory receptor cell differentiation, making it a unique system for studying the molecular mechanisms controlling the switch between proliferation and differentiation. Here we identify the Yap/Tead complex as a key regulator of the self-renewal gene network in organ of Corti progenitor cells. We show that Tead transcription factors bind directly to the putative regulatory elements of many stemness- and cell cycle-related genes. We also show that the Tead coactivator protein, Yap, is degraded specifically in the Sox2-positive domain of the cochlear duct, resulting in down-regulation of Tead gene targets. Further, conditional loss of theYapgene in the inner ear results in the formation of significantly smaller auditory and vestibular sensory epithelia, while conditional overexpression of a constitutively active version ofYap,Yap5SA, is sufficient to prevent cell cycle exit and to prolong sensory tissue growth. We also show that viral gene delivery ofYap5SAin the postnatal inner ear sensory epithelia in vivo drives cell cycle reentry after hair cell loss. Taken together, these data highlight the key role of the Yap/Tead transcription factor complex in maintaining inner ear progenitors during development, and suggest new strategies to induce sensory cell regeneration.
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Ortega, Ángel, Ivana Vera, Maria Diaz, Carla Navarro, Milagros Rojas, Wheeler Torres, Heliana Parra, Juan Salazar, Juan De Sanctis, and Valmore Bermúdez. "The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises." International Journal of Molecular Sciences 23, no. 1 (December 31, 2021): 430. http://dx.doi.org/10.3390/ijms23010430.
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The yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, members of the Hippo signaling pathway, which play a critical role in cell growth regulation, embryonic development, regeneration, proliferation, and cancer origin and progression. The mechanism involves the nuclear binding of the un-phosphorylated YAP/TAZ complex to release the transcriptional enhanced associate domain (TEAD) from its repressors. The active ternary complex is responsible for the aforementioned biological effects. Overexpression of YAP/TAZ has been reported in cancer stem cells and tumor resistance. The resistance involves chemotherapy, targeted therapy, and immunotherapy. This review provides an overview of YAP/TAZ pathways’ role in carcinogenesis and tumor microenvironment. Potential therapeutic alternatives are also discussed.
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Che, Kepeng, Ajaybabu V. Pobbati, Caleb N. Seavey, Yuriy Fedorov, Anton A. Komar, Ashley Burtscher, Shuang Ma, and Brian P. Rubin. "Aurintricarboxylic acid is a canonical disruptor of the TAZ-TEAD transcriptional complex." PLOS ONE 17, no. 4 (April 13, 2022): e0266143. http://dx.doi.org/10.1371/journal.pone.0266143.
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Disrupting the formation of the oncogenic YAP/TAZ-TEAD transcriptional complex holds substantial therapeutic potential. However, the three protein interaction interfaces of this complex cannot be easily disrupted using small molecules. Here, we report that the pharmacologically active small molecule aurintricarboxylic acid (ATA) acts as a disruptor of the TAZ-TEAD complex. ATA was identified in a high-throughput screen using a TAZ-TEAD AlphaLISA assay that was tailored to identify disruptors of this transcriptional complex. We further used fluorescence polarization assays both to confirm disruption of the TAZ-TEAD complex and to demonstrate that ATA binds to interface 3. We have previously shown that cell-based models that express the oncogenic TAZ-CAMTA1 (TC) fusion protein display enhanced TEAD transcriptional activity because TC functions as an activated form of TAZ. Utilizing cell-based studies and our TC model system, we performed TC/TEAD reporter, RNA-Seq, and qPCR assays and found that ATA inhibits TC/TEAD transcriptional activity. Further, disruption of TC/TEAD and TAZ/TEAD interaction by ATA abrogated anchorage-independent growth, the phenotype most closely linked to dysregulated TAZ/TEAD activity. Therefore, this study demonstrates that ATA is a novel small molecule that has the ability to disrupt the undruggable TAZ-TEAD interface.
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Zhang, Dingwa, Deyong He, Xiaoliang Pan, and Lijun Liu. "Rational Design and Intramolecular Cyclization of Hotspot Peptide Segments at YAP–TEAD4 Complex Interface." Protein & Peptide Letters 27, no. 10 (November 2, 2020): 999–1006. http://dx.doi.org/10.2174/0929866527666200414160723.
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Background: The Yes-Associated Protein (YAP) is a central regulator of Hippo pathway involved in carcinogenesis, which functions through interaction with TEA Domain (TEAD) transcription factors. Pharmacological disruption of YAP–TEAD4 complexes has been recognized as a potential therapeutic strategy against diverse cancers by suppressing the oncogenic activity of YAP. Objective: Two peptides, termed PS-1 and PS-2 are split from the interfacial context of YAP protein. Dynamics simulations, energetics analyses and fluorescence polarizations are employed to characterize the intrinsic disorder as well as binding energy/affinity of the two YAP peptides to TEAD4 protein. Methods: Two peptides, termed PS-1 and PS-2 are split from the interfacial context of YAP protein. Dynamics simulations, energetics analyses and fluorescence polarizations are employed to characterize the intrinsic disorder as well as binding energy/affinity of the two YAP peptides to TEAD4 protein. Result: The native conformation of PS-2 peptide is a cyclic loop, which is supposed to be constrained by adding a disulfide bond across the spatially vicinal residue pair Arg87-Phe96 or Met86- Phe95 at the peptide’s two ends, consequently resulting in two intramolecular cyclized counterparts of linear PS-2 peptide, namely PS-2(cyc87,96) and PS-2(cyc86,95). The linear PS-2 peptide is determined as a weak binder of TEAD4 (Kd = 190 μM), while the two cyclic PS-2(cyc87,96) and PS-2(cyc86,95) peptides are measured to have moderate or high affinity towards TEAD4 (Kd = 21 and 45 μM, respectively). Conclusion: PS-1 and PS-2 peptides are highly flexible and cannot maintain in native active conformation when splitting from the interfacial context, and thus would incur a considerable entropy penalty upon rebinding to the interface. Cyclization does not influence the direct interaction between PS-2 peptide and TEAD4 protein, but can largely reduce the intrinsic disorder of PS-2 peptide in free state and considerably minimize indirect entropy effect upon the peptide binding.
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Bhat, Krishna, Krishna Bhat, and Tiffany Tang. "DNAR-05. A ROLE FOR TAZ/YAP IN DNA DAMAGE REPAIR IN GLIOBLASTOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii91. http://dx.doi.org/10.1093/neuonc/noac209.337.
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Abstract Previous studies have shown that glioma stem-like cells (GSCs) evade conventional cytotoxic therapies and repopulate as recurrent tumors. A fuller understanding of the molecular mechanisms underlying the biology and therapy resistance of GSCs is required. Our group has shown that TAZ, a transcriptional co-factor is highly expressed in about 70% of glioblastomas (GBMs). TAZ and its paralog YAP are oncogenic drivers of brain tumor progression. GSCs overexpressing TAZ undergo a proneural (PN) to mesenchymal (MS) subtype transition, which is accompanied by aggressive phenotypes such as increased grade and treatment resistance in GSC xenografts. Although the oncogenic functions of TAZ/YAP are well established, the exact molecular mechanisms underlying TAZ/YAP mediated cell fate transition and therapy resistance in GBM are not fully understood. Here, we present novel functional interaction between TAZ/YAP and DNA-dependent protein kinase (DNA-PK) in response to exposure to ionizing radiation in GSCs. Mass-spectrometric analyses of TAZ-binding proteins showed that DNA-PK complex composed of the catalytic subunit (DNA-PKcs) and a Ku heterodimer of Ku70 and K80 interacted with TAZ. Immunoprecipitation of DNA-PK showed interaction of both YAP as well. Interaction of YAP/TAZ with DNA-PK complex and TEAD was enhanced by ionizing radiation. DNA-PKcs phosphorylated both YAP and TAZ, and phosphorylation level of these proteins were increased after irradiation, consistent with an increased interaction of these proteins. Intriguingly, siRNA knockdown of YAP and TAZ resulted in inactivation of DNA-PKcs, although protein stability of DNA-PKcs was not affected. Pharmacological inhibition of TAZ/YAPTEAD resulted in increased DNA damage and suppressed cell proliferation, and this effect was synergized by irradiation. We conclude that TAZ and YAP are integral components of DNA damage response and that pharmacological targeting of TAZ/YAP/TEAD pathway can overcome radiation resistance in GSCs.
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Liu-Chittenden, Y., B. Huang, J. S. Shim, Q. Chen, S. J. Lee, R. A. Anders, J. O. Liu, and D. Pan. "Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP." Genes & Development 26, no. 12 (June 7, 2012): 1300–1305. http://dx.doi.org/10.1101/gad.192856.112.
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Kamal, Adeela, Aurélie Candi, Matthias Versele, Bart Vanderhoydonck, Arnaud Marchand, Ron de Jong, Thuy Hoang, et al. "Abstract 3945: Novel antagonists of TEAD palmitoylation inhibit the growth of Hippo-altered cancers in preclinical models." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3945. http://dx.doi.org/10.1158/1538-7445.am2022-3945.
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Abstract Background: The Hippo pathway is an evolutionarily conserved signaling cascade whose deregulation can promote excessive cell proliferation and tumor development. Pathway output is mediated by the YAP and TAZ transcriptional co-activators, which bind to TEAD family transcription factors to drive target gene expression. Genomic aberrations in Hippo pathway components result in constitutive activation of YAP/TAZ, as seen with NF2 mutations in subsets of mesothelioma and other cancers. Hyperactivation of YAP/TAZ has also been associated with resistance to a variety of targeted agents, including EGFR and CDK4/6 inhibitors, suggesting that targeting the pathway may have utility as part of rationally selected combinations, in addition to genomically-informed monotherapy applications. Activity of the YAP/TAZ-TEAD complex thus represents a compelling pharmacologic target, due to its essential role in the pathway, and the presence of a conserved druggable site in TEAD that is required for transcriptional function. Results and Discussion: Using biophysical techniques, we identified novel small molecules that bind to the TEAD auto-palmitoylation pocket. Initial hits were optimized for antagonism of TEAD-based transcription and drug-like properties, ultimately producing highly potent and orally bioavailable TEAD inhibitors. These compounds selectively inhibited the proliferation of cancer cell lines harboring genomic alterations in the Hippo pathway with low nM potency. In vivo models of Hippo pathway-altered xenografts showed consistent monotherapy activity, with dose-dependent and durable tumor regressions achieved at well-tolerated doses. Further characterization of these compounds as monotherapies and as part of rationally-designed combination regimens is ongoing. Citation Format: Adeela Kamal, Aurélie Candi, Matthias Versele, Bart Vanderhoydonck, Arnaud Marchand, Ron de Jong, Thuy Hoang, Georg Halder, Patrick Chaltin, Stephen L. Gwaltney, Mike Burgess. Novel antagonists of TEAD palmitoylation inhibit the growth of Hippo-altered cancers in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3945.
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Rogg, Manuel, Jasmin I. Maier, Martin Helmstädter, Alena Sammarco, Felix Kliewe, Oliver Kretz, Lisa Weißer, et al. "A YAP/TAZ–ARHGAP29–RhoA Signaling Axis Regulates Podocyte Protrusions and Integrin Adhesions." Cells 12, no. 13 (July 6, 2023): 1795. http://dx.doi.org/10.3390/cells12131795.
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Glomerular disease due to podocyte malfunction is a major factor in the pathogenesis of chronic kidney disease. Identification of podocyte-specific signaling pathways is therefore a prerequisite to characterizing relevant disease pathways and developing novel treatment approaches. Here, we employed loss of function studies for EPB41L5 (Yurt) as a central podocyte gene to generate a cell type-specific disease model. Loss of Yurt in fly nephrocytes caused protein uptake and slit diaphragm defects. Transcriptomic and proteomic analysis of human EPB41L5 knockout podocytes demonstrated impaired mechanotransduction via the YAP/TAZ signaling pathway. Further analysis of specific inhibition of the YAP/TAZ-TEAD transcription factor complex by TEADi led to the identification of ARGHAP29 as an EPB41L5 and YAP/TAZ-dependently expressed podocyte RhoGAP. Knockdown of ARHGAP29 caused increased RhoA activation, defective lamellipodia formation, and increased maturation of integrin adhesion complexes, explaining similar phenotypes caused by loss of EPB41L5 and TEADi expression in podocytes. Detection of increased levels of ARHGAP29 in early disease stages of human glomerular disease implies a novel negative feedback loop for mechanotransductive RhoA—YAP/TAZ signaling in podocyte physiology and disease.
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Kim, Jongwan, Hocheol Lim, Sungho Moon, Seon Yeon Cho, Minhye Kim, Jae Hyung Park, Hyun Woo Park, and Kyoung Tai No. "Hot Spot Analysis of YAP-TEAD Protein-Protein Interaction Using the Fragment Molecular Orbital Method and Its Application for Inhibitor Discovery." Cancers 13, no. 16 (August 23, 2021): 4246. http://dx.doi.org/10.3390/cancers13164246.
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The Hippo pathway is an important signaling pathway modulating growth control and cancer cell proliferation. Dysregulation of the Hippo pathway is a common feature of several types of cancer cells. The modulation of the interaction between yes-associated protein (YAP) and transcriptional enhancer associated domain (TEAD) in the Hippo pathway is considered an attractive target for cancer therapeutic development, although the inhibition of PPI is a challenging task. In order to investigate the hot spots of the YAP and TEAD1 interacting complex, an ab initio Fragment Molecular Orbital (FMO) method was introduced. With the hot spots, pharmacophores for the inhibitor design were constructed, then virtual screening was performed to an in-house library. Next, we performed molecular docking simulations and FMO calculations for screening results to study the binding modes and affinities between PPI inhibitors and TEAD1. As a result of the virtual screening, three compounds were selected as virtual hit compounds. In order to confirm their biological activities, cellular (luciferase activity, proximity ligation assay and wound healing assay in A375 cells, qRT-PCR in HEK 293T cells) and biophysical assays (surface plasmon resonance assays) were performed. Based on the findings of the study, we propose a novel PPI inhibitor BY03 and demonstrate a profitable strategy to analyze YAP–TEAD PPI and discover novel PPI inhibitors.
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Huang, Yunying, Usama Sharif Ahmad, Ambreen Rehman, Jutamas Uttagomol, and Hong Wan. "YAP Inhibition by Verteporfin Causes Downregulation of Desmosomal Genes and Proteins Leading to the Disintegration of Intercellular Junctions." Life 12, no. 6 (May 26, 2022): 792. http://dx.doi.org/10.3390/life12060792.
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The Hippo-YAP pathway serves as a central signalling hub in epithelial tissue generation and homeostasis. Yes-associated protein (YAP) is an essential downstream transcription cofactor of this pathway, with its activity being negatively regulated by Hippo kinase-mediated phosphorylation, leading to its cytoplasmic translocation or degradation. Our recent study showed phospho-YAP complexes with Desmoglein-3 (Dsg3), the desmosomal cadherin known to be required for junction assembly and cell–cell adhesion. In this study, we show that YAP inhibition by Verteporfin (VP) caused a significant downregulation of desmosomal genes and a remarkable reduction in desmosomal proteins, including the Dsg3/phospho-YAP complex, resulting in attenuation of cell cohesion. We also found the desmosomal genes, along with E-cadherin, were the YAP-TEAD transcriptional targets and Dsg3 regulated key Hippo components, including WWTR1/TAZ, LATS2 and the key desmosomal molecules. Furthermore, Dsg3 and phospho-YAP exhibited coordinated regulation in response to varied cell densities and culture durations. Overexpression of Dsg3 could compensate for VP mediated loss of adhesion components and proper architecture of cell junctions. Thus, our findings suggest that Dsg3 plays a crucial role in the Hippo network and regulates junction configuration via complexing with phospho-YAP.
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Li, Jie Jack, Guiping Zhang, and Jiapeng Li. "Abstract 3401: Discovery of GH658, a novel tead allosteric inhibitor as a cancer therapy." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3401. http://dx.doi.org/10.1158/1538-7445.am2023-3401.
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Abstract The Hippo pathway is an evolutionarily conserved signaling cascade. Its dysregulation may lead to cancer progression, metastasis, cancer therapy resistance, and immune evasion. Diverse genetic aberrations leading to YAP/TAZ hyperactivation have been elucidated over the last 20 years. Almost all the pro-tumor mutations lead to constitutive TEAD transcription factor activation, suggesting that targeting TEAD transcription factors could offer an important therapeutic opportunity. Employing structure-based drug design, we have discovered GH658, a novel allosteric TEAD inhibitor that selectively targets the auto-palmitoylation pocket of TEAD proteins. In vitro, GH658 displayed a low nM potency in TEAD-based reporter assays, which translated to specific low nM inhibition of NF2 deficient mesothelioma proliferation. In vivo, GH658 demonstrated favorable pharmacokinetic properties in different species and showed acceptable safety profile. Furthermore, daily oral dosing of GH658 led to complete growth inhibition of NF2 mutant xenograft tumors without adverse effect on body weight. More importantly, GH658 displayed significant in vivo effect on drug tolerant persistent cancer cells and drug resistance against inhibitors targeting EGFR‒RAS signaling pathways in combination studies. In summary, with potent in vitro and in vivo efficacy of targeting YAP/TAZ‒TEAD transcriptional complex, GH658 not only showed consistent monotherapy activity in selected cancer models, but also demonstrated significant synergistic effects in diverse drug combination studies. Citation Format: Jie Jack Li, Guiping Zhang, Jiapeng Li. Discovery of GH658, a novel tead allosteric inhibitor as a cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3401.
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Zhang, Wenxiang, Jinjin Xu, Jinhui Li, Tong Guo, Dan Jiang, Xue Feng, Xueyan Ma, et al. "The TEA domain family transcription factor TEAD4 represses murine adipogenesis by recruiting the cofactors VGLL4 and CtBP2 into a transcriptional complex." Journal of Biological Chemistry 293, no. 44 (September 12, 2018): 17119–34. http://dx.doi.org/10.1074/jbc.ra118.003608.
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The Hippo signaling pathway is known to play an important role in multiple physiological processes, including adipogenesis. However, whether the downstream components of the Hippo pathway are involved in adipogenesis remains unknown. Here we demonstrate that the TEA domain family (TEAD) transcription factors are essential for adipogenesis in murine 3T3-L1 preadipocytes. Knockdown of TEAD1–4 stimulated adipogenesis and increased the expression of adipocyte markers in these cells. Interestingly, we found that the TEAD4 knockdown–mediated adipogenesis proceeded in a Yes-associated protein (YAP)/TAZ (Wwtr1)–independent manner and that adipogenesis suppression in WT cells involved formation of a ternary complex comprising TEAD4 and the transcriptional cofactors C-terminal binding protein 2 (CtBP2) and vestigial-like family member 4 (VGLL4). VGLL4 acted as an adaptor protein that enhanced the interaction between TEAD4 and CtBP2, and this TEAD4–VGLL4–CtBP2 ternary complex dynamically existed at the early stage of adipogenesis. Finally, we verified that TEAD4 directly targets the promoters of major adipogenesis transcription factors such as peroxisome proliferator–activated receptor γ (PPARγ) and adiponectin, C1Q, and collagen domain–containing (Adipoq) during adipogenesis. These findings reveal critical insights into the role of the TEAD4–VGLL4–CtBP2 transcriptional repressor complex in suppression of adipogenesis in murine preadipocytes.
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Qiao, Y., S. J. Lin, Y. Chen, D. C.-C. Voon, F. Zhu, L. S. H. Chuang, T. Wang, et al. "RUNX3 is a novel negative regulator of oncogenic TEAD–YAP complex in gastric cancer." Oncogene 35, no. 20 (September 14, 2015): 2664–74. http://dx.doi.org/10.1038/onc.2015.338.
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Chen, Liming, Portia Gloria Loh, and Haiwei Song. "Structural and functional insights into the TEAD-YAP complex in the Hippo signaling pathway." Protein & Cell 1, no. 12 (December 2010): 1073–83. http://dx.doi.org/10.1007/s13238-010-0138-3.
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Chien, Chu-Yen, Ying-Chen Chen, Chia-Chen Hsu, Yu-Ting Chou, Shine-Gwo Shiah, Shyun-Yeu Liu, Alexander Cheng-Ting Hsieh, Ching-Yu Yen, Chien-Hsing Lee, and Yi-Shing Shieh. "YAP-Dependent BiP Induction Is Involved in Nicotine-Mediated Oral Cancer Malignancy." Cells 10, no. 8 (August 13, 2021): 2080. http://dx.doi.org/10.3390/cells10082080.
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Cigarette smoking is a significant risk factor for the development and progression of oral cancer. Previous studies have reported an association between nicotine and malignancy in oral cancer. Recent studies have also demonstrated that nicotine can induce endoplasmic reticulum (ER) stress in tumor cells. Binding immunoglobulin protein (BiP) acts as a master regulator of ER stress and is frequently overexpressed in oral cancer cell lines and tissues. However, the effect of nicotine on BiP in oral cancer is unknown. Therefore, this study aimed to evaluate the role of BiP and its underlying regulatory mechanisms in nicotine-induced oral cancer progression. Our results showed that nicotine significantly induced the expression of BiP in time- and dose-dependent manners in oral squamous cell carcinoma (OSCC) cells. In addition, BiP was involved in nicotine-mediated OSCC malignancy, and depletion of BiP expression remarkably suppressed nicotine-induced malignant behaviors, including epithelial–mesenchymal transition (EMT) change, migration, and invasion. In vivo, BiP silencing abrogated nicotine-induced tumor growth and EMT switch in nude mice. Moreover, nicotine stimulated BiP expression through the activation of the YAP-TEAD transcriptional complex. Mechanistically, we observed that nicotine regulated YAP nuclear translocation and its interaction with TEAD through α7-nAChR-Akt signaling, subsequently resulting in increased TEAD occupancy on the HSPA5 promoter and elevated promoter activity. These observations suggest that BiP is involved in nicotine-induced oral cancer malignancy and may have therapeutic potential in tobacco-related oral cancer.
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Kohli, Priyanka, Malte P. Bartram, Sandra Habbig, Caroline Pahmeyer, Tobias Lamkemeyer, Thomas Benzing, Bernhard Schermer, and Markus M. Rinschen. "Label-free quantitative proteomic analysis of the YAP/TAZ interactome." American Journal of Physiology-Cell Physiology 306, no. 9 (May 1, 2014): C805—C818. http://dx.doi.org/10.1152/ajpcell.00339.2013.
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The function of an individual protein is typically defined by protein-protein interactions orchestrating the formation of large complexes critical for a wide variety of biological processes. Over the last decade the analysis of purified protein complexes by mass spectrometry became a key technique to identify protein-protein interactions. We present a fast and straightforward approach for analyses of interacting proteins combining a Flp-in single-copy cellular integration system and single-step affinity purification with single-shot mass spectrometry analysis. We applied this protocol to the analysis of the YAP and TAZ interactome. YAP and TAZ are the downstream effectors of the mammalian Hippo tumor suppressor pathway. Our study provides comprehensive interactomes for both YAP and TAZ and does not only confirm the majority of previously described interactors but, strikingly, revealed uncharacterized interaction partners that affect YAP/TAZ TEAD-dependent transcription. Among these newly identified candidates are Rassf8, thymopoetin, and the transcription factors CCAAT/enhancer-binding protein (C/EBP)β/δ and core-binding factor subunit β (Cbfb). In addition, our data allowed insights into complex stoichiometry and uncovered discrepancies between the YAP and TAZ interactomes. Taken together, the stringent approach presented here could help to significantly sharpen the understanding of protein-protein networks.
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Sudhir, Sweta, Maria Anastasiadou, Gabrielle Price, and Constantinos Hadjipanayis. "CSIG-18. ANTI-TUMOR EFFECTS OF VERTEPORFIN AND PHOTODYNAMIC THERAPY IN COMBINATION WITH STANDARD OF CARE ON PATIENT-DERIVED GBM CELL LINES." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii42—vii43. http://dx.doi.org/10.1093/neuonc/noac209.167.
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Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median survival of approximately 15 months. GBM tumorigenicity frequently arises from aberrant signaling transduction pathways involving receptor tyrosine kinases (RTKs), such as EGFR and PI3K. Amplification of the Epidermal Growth Factor Receptor (EGFR) gene upregulates Hippo pathway transcription factors YAP1 and TAZ, leading to tumor cell proliferation, radiation resistance, and poor survival. Verteporfin (VP), also known as Visudyne, is an FDA-approved macular degeneration photosensitizer that has photodynamic effects when combined with 489 nm of light. Additionally, VP is a small-molecule inhibitor of the YAP/TAZ/TEAD complex that has been shown to reduce tumor migration and is in phase I clinical trial as a chemotherapeutic for patients with recurrent GBM. We now investigate if VP is an effective photosensitizer for PDT in GBM and if it enhances the effects of TMZ and RT. Compared to VP alone, VP+PDT reduced the IC50 of VP treatment in GBM cells +/- EGFR amplification. Light activation of VP has a significant antitumor effect as observed with cytotoxicity in comparison to vehicle and VP treated cells (p< 0.01). Compared to control, VP, VP+PDT+TMZ, and CRT show significantly less intravasation (p< 0.01). Furthermore, Western blot analysis shows differential expression of YAP, TAZ and TEAD compared to Control and VP after treatment with VP+PDT. Differential YAP signaling is observed via IF staining in EGFR+ GBM cells treat with VP+PDT. Our research supports the use of VP as a photosensitizer in GBM cells. We found downregulation of the hippo pathway and decrease tumorigenicity of GBM cells. Application of VP-PDT treatment in combination with standard of care may be proven beneficial in GBM patients. We plan to further explore these in vitro findings in mice models and investigate other pathways including immune response with NanoString analysis.
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Chen, Jianchun, Huaizhou You, Yan Li, You Xu, Qian He, and Raymond C. Harris. "EGF Receptor–Dependent YAP Activation Is Important for Renal Recovery from AKI." Journal of the American Society of Nephrology 29, no. 9 (August 2, 2018): 2372–85. http://dx.doi.org/10.1681/asn.2017121272.
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BackgroundIncreasing evidence indicates that renal recovery from AKI stems from dedifferentiation and proliferation of surviving tubule epithelial cells. Both EGF receptor (EGFR) and the Hippo signaling pathway are implicated in cell proliferation and differentiation, and previous studies showed that activation of EGFR in renal proximal tubule epithelial cells (RPTCs) plays a critical role in recovery from ischemia-reperfusion injury (IRI). In this study, we explored RPTC activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ), two key downstream effectors of the Hippo pathway, and their potential involvement in recovery from AKI.MethodsWe used immunofluorescence to examine YAP expression in kidney biopsy samples from patients with clinical AKI and controls (patients with minimal change disease). Studies of RPTC activation of YAP and TAZ used cultured human RPTCs that were exposed to hypoxia-reoxygenation as well as knockout mice (with inducible deletions of Yap, Taz, or both occurring specifically in RPTCs) that were subjected to bilateral IRI.ResultsYAP was activated in RPTCs in kidneys from post-AKI patients and post-IRI mouse kidneys. Inhibition of the interaction of YAP and the TEA domain (TEAD) transcription factor complex by verteporfin or conditional deletion of YAP in RPTCs delayed renal functional and structural recovery from IRI, whereas TAZ deletion had no effect. Activation of the EGFR-PI3K-Akt pathway in response to IRI signaled YAP activation, which promoted cell cycle progression.ConclusionsThis study shows that EGFR-PI3K-Akt–dependent YAP activation plays an essential role in mediating epithelial cell regeneration during kidney recovery from AKI.
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Li, Zhengyu, Juntao Feng, Jinhai Gou, Jia Jia, Tao Yi, and Tao Cui. "Verteporfin, a suppressor of YAP–TEAD complex, presents promising antitumor properties on ovarian cancer." OncoTargets and Therapy Volume 9 (August 2016): 5371–81. http://dx.doi.org/10.2147/ott.s109979.
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Clattenburg, Leanne, Michael Wigerius, Jiansong Qi, Jan K. Rainey, Jillian L. Rourke, Shanmugam Muruganandan, Christopher J. Sinal, and James P. Fawcett. "NOS1AP Functionally Associates with YAP To Regulate Hippo Signaling." Molecular and Cellular Biology 35, no. 13 (April 27, 2015): 2265–77. http://dx.doi.org/10.1128/mcb.00062-15.
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Deregulation of cellular polarity proteins and their associated complexes leads to changes in cell migration and proliferation. The nitric oxide synthase 1 adaptor protein (NOS1AP) associates with the tumor suppressor protein Scribble to control cell migration and oncogenic transformation. However, how NOS1AP is linked to the cell signaling events that curb oncogenic progression has remained elusive. Here we identify several novel NOS1AP isoforms, NOS1APd, NOS1APe, and NOS1APf, with distinct cellular localizations. We show that isoforms with a membrane-interacting phosphotyrosine binding (PTB) domain can associate with Scribble and recognize acidic phospholipids. In a screen to identify novel binding proteins, we have discovered a complex consisting of NOS1AP and the transcriptional coactivator YAP linking NOS1AP to the Hippo signaling pathway. Silencing of NOS1AP reduces the phosphorylation of YAP and of the upstream kinase Lats1. Conversely, expression of NOS1AP promotes YAP and Lats1 phosphorylation, which correlates with reduced TEAD activity and restricted cell proliferation. Together, these data implicate a role for NOS1AP in the regulation of core Hippo signaling and are consistent with the idea that NOS1AP functions as a tumor suppressor.
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Wolfe, Andrew L., Qingwen Zhou, Eneda Toska, Jacqueline Galeas, Angel A. Ku, Richard P. Koche, Sourav Bandyopadhyay, et al. "UDP-glucose pyrophosphorylase 2, a regulator of glycogen synthesis and glycosylation, is critical for pancreatic cancer growth." Proceedings of the National Academy of Sciences 118, no. 31 (July 30, 2021): e2103592118. http://dx.doi.org/10.1073/pnas.2103592118.
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UDP-glucose pyrophosphorylase 2 (UGP2), the enzyme that synthesizes uridine diphosphate (UDP)-glucose, rests at the convergence of multiple metabolic pathways, however, the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an important role for UGP2 in the maintenance of pancreatic ductal adenocarcinoma (PDAC) growth in both in vitro and in vivo tumor models. We found that transcription of UGP2 is directly regulated by the Yes-associated protein 1 (YAP)–TEA domain transcription factor (TEAD) complex, identifying UGP2 as a bona fide YAP target gene. Loss of UGP2 leads to decreased intracellular glycogen levels and defects in N-glycosylation targets that are important for the survival of PDACs, including the epidermal growth factor receptor (EGFR). These critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer insights into therapeutic options for otherwise intractable PDACs.
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Zhou, Xiangxiang, Juan Yang, Ya Zhang, Ying Li, Xiaosheng Fang, Na Chen, and Xin Wang. "Blockade of Yes-Associated Protein As a Novel Therapeutic Approach in Diffuse Large B-Cell Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 808. http://dx.doi.org/10.1182/blood-2019-129695.
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Introduction Yes-associated protein (YAP) is an important transcriptional regulator and effector of the Hippo signaling that has emerged as a novel determinant of malignancy in several human tumors. Verteporfin (VP), a clinically used photosensitizer for treatment of macular degeneration, is recently identified as a potential inhibitor of YAP expression independent of light activation. However, the function and mechanism of Hippo-YAP in diffuse large B-cell lymphoma (DLBCL) remains ill defined. Herein, we investigated the functional significance of YAP and proposed a novel therapeutic strategy for DLBCL. Methods Lymph node biopsies from 60 de novo DLBCL patients and 30 reactive hyperplasia cases were collected with informed consents. The biological function of YAP was evaluated via RNAi-mediated knockdown and CRISPR/Cas9 mediated genomic deletion. RNA-sequencing was conducted to detect the dysregulated RNAs in DLBCL cell with YAP knockout. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analyses were used to explore the function of these differentially expressed RNAs. SCID-Beige mice were subcutaneously injected with DLBCL cells to establish xenograft model. Animal experiments were performed in accordance with the principles of the Institutional Animal Care. Results We first examined the expression of YAP in Oncomine database and discovered the upregulation of YAP mRNA in DLBCL cells (Fig.1A). High expression of YAP protein was validated in a cohort of newly diagnosed DLBCL patients (n=60). Survival analysis revealed that YAP expression was associated with aggressive disease process (p=0.014, Fig.1B). Functional enrichment analyses of YAP in DLBCL microarray profiles revealed that YAP was enriched in cellular process and biological regulation (Fig. 1C). Knockdown of YAP (shYAP) significantly suppressed cell proliferation and promoted cell cycle arrest (Fig.2A-C). VP restrained proliferation of DLBCL cells in a dose- and time-dependent manner (Fig. 2D). Treatment of VP significantly promoted cell apoptosis and cell cycle arrest in DLBCL cells (Fig. 2E). We next validated the involved mechanism of the anti-tumor effect of VP in DLBCL cells. Protein expression levels of YAP and TEAD were significantly inhibited by VP in dose-dependent manner (Fig.2F). In addition, treatment of VP remarkably restrained the mRNA expression of YAP targeted genes, including CTGF, CYR61 and NF2 (Fig. 2G). Genomic network enrichment of YAP interactions was established in STRING database (Fig. 2H). To validate the involvement of YAP in DLBCL pathogenesis, we deleted YAP expression by CRISPR/Cas9 genomic-editing system. YAP deletion (sgYAP) resulted in significantly reduction in cell proliferation and arrest of cell cycle (Fig.3A). To explore the activities of YAP inhibition in vivo, xenograft DLBCL mice model was established by LY1 cells with YAP-deletion. Compared to the control group, tumors with YAP-deletion displayed reduced growth and decreased expression levels of Ki67 and C-myc (Fig. 3B-C). To further explore the translational regulation mechanism of YAP in DLBCL, integrated analysis of mRNA and non-coding RNA (ncRNA) expression profiles were conducted by whole-transcriptome sequencing (RNA-seq). 158 miRNAs, 29 lncRNAs, 74 circRNAs and 528 mRNAs were shown to be significantly differentially expressed (DE) in DLBCL cells with YAP knockout (Fig. 4A-C). The subsequent GO and KEGG pathway analysis revealed that DE molecules mainly related to cellular metabolic process and pathways. In addition, the miRNA-circRNA network was established (Fig. 4D). Conclusion Taken together, these findings provide in vitro and in vivo pre-clinical evidence for the crucial role of YAP in lymphomagenesis and highlight that blockade of YAP represents an attractive approach in DLBCL. The clinical used photosensitizer Verteporfin exerted anti-tumor effect via disrupting YAP-TEAD complex. Further interrogation on the regulatory mechanism of YAP in DLBCL will outline a promising therapeutic option to utilize this newly identified oncogene in DLBCL therapy. Disclosures No relevant conflicts of interest to declare.
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Cunningham, Richard, and Carsten Gram Hansen. "The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer." Clinical Science 136, no. 3 (February 2022): 197–222. http://dx.doi.org/10.1042/cs20201474.
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Abstract Tumorigenesis is a highly complex process, involving many interrelated and cross-acting signalling pathways. One such pathway that has garnered much attention in the field of cancer research over the last decade is the Hippo signalling pathway. Consisting of two antagonistic modules, the pathway plays an integral role in both tumour suppressive and oncogenic processes, generally via regulation of a diverse set of genes involved in a range of biological functions. This review discusses the history of the pathway within the context of cancer and explores some of the most recent discoveries as to how this critical transducer of cellular signalling can influence cancer progression. A special focus is on the various recent efforts to therapeutically target the key effectors of the pathway in both preclinical and clinical settings.
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Bokhovchuk, Fedir, Yannick Mesrouze, Marco Meyerhofer, Catherine Zimmermann, Patrizia Fontana, Dirk Erdmann, Per Jemth, and Patrick Chène. "An Early Association between the α-Helix of the TEAD Binding Domain of YAP and TEAD Drives the Formation of the YAP:TEAD Complex." Biochemistry 59, no. 19 (April 24, 2020): 1804–12. http://dx.doi.org/10.1021/acs.biochem.0c00217.
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Bi-Lin, Kathleen Wung, Pratap Veerabrahma Seshachalam, Tran Tuoc, Anastassia Stoykova, Sujoy Ghosh, and Manvendra K. Singh. "Critical role of the BAF chromatin remodeling complex during murine neural crest development." PLOS Genetics 17, no. 3 (March 22, 2021): e1009446. http://dx.doi.org/10.1371/journal.pgen.1009446.
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The BAF complex plays an important role in the development of a wide range of tissues by modulating gene expression programs at the chromatin level. However, its role in neural crest development has remained unclear. To determine the role of the BAF complex, we deleted BAF155/BAF170, the core subunits required for the assembly, stability, and functions of the BAF complex in neural crest cells (NCCs). Neural crest-specific deletion ofBAF155/BAF170leads to embryonic lethality due to a wide range of developmental defects including craniofacial, pharyngeal arch artery, and OFT defects. RNAseq and transcription factor enrichment analysis revealed that the BAF complex modulates the expression of multiple signaling pathway genes including Hippo and Notch, essential for the migration, proliferation, and differentiation of the NCCs. Furthermore, we demonstrated that the BAF complex is essential for the Brg1-Yap-Tead-dependent transcription of target genes in NCCs. Together, our results demonstrate an important role of the BAF complex in modulating the gene regulatory network essential for neural crest development.
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Sileo, Pasquale, Clémence Simonin, Patricia Melnyk, Marie-Christine Chartier-Harlin, and Philippe Cotelle. "Crosstalk between the Hippo Pathway and the Wnt Pathway in Huntington’s Disease and Other Neurodegenerative Disorders." Cells 11, no. 22 (November 16, 2022): 3631. http://dx.doi.org/10.3390/cells11223631.
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The Hippo pathway consists of a cascade of kinases that controls the phosphorylation of the co-activators YAP/TAZ. When unphosphorylated, YAP and TAZ translocate into the nucleus, where they mainly bind to the TEAD transcription factor family and activate genes related to cell proliferation and survival. In this way, the inhibition of the Hippo pathway promotes cell survival, proliferation, and stemness fate. Another pathway can modulate these processes, namely the Wnt/β-catenin pathway that is indeed involved in cellular functions such as proliferation and cell survival, as well as apoptosis, growth, and cell renewal. Wnt signaling can act in a canonical or noncanonical way, depending on whether β-catenin is involved in the process. In this review, we will focus only on the canonical Wnt pathway. It has emerged that YAP/TAZ are components of the β-catenin destruction complex and that there is a close relationship between the Hippo pathway and the canonical Wnt pathway. Furthermore, recent data have shown that both of these pathways may play a role in neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, or Amyotrophic Lateral Sclerosis. Thus, this review analyzes the Hippo pathway and the Wnt pathway, their crosstalk, and their involvement in Huntington’s disease, as well as in other neurodegenerative disorders. Altogether, these data suggest possible therapeutic approaches targeting key players of these pathways.
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Kaushik, Itishree, Shreyas Gaikwad, and Sanjay K. Srivastava. "Abstract 3895: Moxidectin unravels the role of Hippo-YAP pathway in maintaining immunity of pediatric glioblastoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3895. http://dx.doi.org/10.1158/1538-7445.am2022-3895.
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Abstract Pediatric glioblastoma multiforme (GBM) is considered to be the second most lethal childhood cancer type after leukemia. Recent preclinical, clinical and genomic studies have highlighted upon the role of Hippo-Yap pathway in the progression of pediatric GBM. In addition, recent studies have established the role of YAP in creating immune suppressive tumor microenvironment (TME) facilitating drug resistance, recurrence and metastasis of GBM tumors. Herein, we report that ‘moxidectin’ an anti-helminthic drug inhibits the proliferation of SF268, SF295, SF188 and CT-2A Luc GBM cells by inducing apoptosis. Immunoblotting and immunofluorescence microscopy studies show that moxidectin mediates its effects by inhibiting MEK-ERK pathway, a regulator of Hippo-YAP signaling. As a result, moxidectin suppressed the nuclear translocation and transcriptional activity of YAP/TAZ-TEAD complex. Oral administration of 3.5mg/kg moxidectin suppressed the growth of GBM tumors by 90% in intracranial tumor model. Ex-vivo analysis of excised tumors confirmed the observations made in in vitro studies. We further conducted immunophenotyping on the excised tumors from both control and moxidectin treated mice to evaluate the effect of moxidectin on immune cell markers in TME and Tumor Draining Lymph Nodes (TDLNs). Our analysis indicated that treatment with moxidectin suppressed the immune suppressive TME created by GBM tumor. Interestingly, moxidectin enhanced antigen presentation in the TDLN. Indicating that it might play a role in activating the peripheral immune response. Moxidectin is an FDA approved drug and any findings from our research will promote its further investigation as a potential therapeutic agent for GBM patients. Citation Format: Itishree Kaushik, Shreyas Gaikwad, Sanjay K. Srivastava. Moxidectin unravels the role of Hippo-YAP pathway in maintaining immunity of pediatric glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3895.
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Wei, Honglong, Fuhai Wang, Yong Wang, Tao Li, Peng Xiu, Jingtao Zhong, Xueying Sun, and Jie Li. "Verteporfin suppresses cell survival, angiogenesis and vasculogenic mimicry of pancreatic ductal adenocarcinoma via disrupting the YAP-TEAD complex." Cancer Science 108, no. 3 (March 2017): 478–87. http://dx.doi.org/10.1111/cas.13138.
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Zhang, Wenjing, Yijun Gao, Peixue Li, Zhubing Shi, Tong Guo, Fei Li, Xiangkun Han, et al. "VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex." Cell Research 24, no. 3 (January 24, 2014): 331–43. http://dx.doi.org/10.1038/cr.2014.10.
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Zhou, X., X. Fang, N. Chen, K. Lu, X. Lv, and X. Wang. "THE PHOTOSENSITIZER VERTEPORFIN EXERTED ANTI-TUMOR EFFECT IN DIFFUSE LARGE B-CELL LYMPHOMA VIA DISRUPTING YAP-TEAD COMPLEX." Hematological Oncology 37 (June 2019): 514. http://dx.doi.org/10.1002/hon.198_2631.
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Pijuan-Galitó, Sara, Christoffer Tamm, and Cecilia Annerén. "Serum Inter-α-inhibitor Activates the Yes Tyrosine Kinase and YAP/TEAD Transcriptional Complex in Mouse Embryonic Stem Cells." Journal of Biological Chemistry 289, no. 48 (October 9, 2014): 33492–502. http://dx.doi.org/10.1074/jbc.m114.580076.
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Gibault, Floriane, Manon Sturbaut, Mathilde Coevoet, Martine Pugnière, Ashley Burtscher, Frédéric Allemand, Patricia Melnyk, et al. "Design, Synthesis and Evaluation of a Series of 1,5‐Diaryl‐1,2,3‐triazole‐4‐carbohydrazones as Inhibitors of the YAP‐TAZ/TEAD Complex." ChemMedChem 16, no. 18 (July 2021): 2823–44. http://dx.doi.org/10.1002/cmdc.202100153.
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Baitei, Essa Y., Min Zhang, Qianqian Sun, Jin-Li Luo, Philip Zhang, Tamihiro Kamata, James Harber, et al. "Abstract 6086: Clonal biallelic inactivation of NF2 is an evolutionary bottleneck that exposes a vulnerability to CDK7 inhibition in mesothelioma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6086. http://dx.doi.org/10.1158/1538-7445.am2022-6086.
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Abstract Background: Mesothelioma, a cancer caused by asbestos is lethal and lacks molecularly targeted therapy. The tumor suppressor NF2 constitutes a frequent, positively selected somatic alteration warranting synthetic lethal approaches to target this driver. NF2 inactivation drives nuclearization of YAP to mediate TEAD dependent oncogenic transcriptional program. YAP is stabilized by CDK7 through phosphorylation of S169/S128/S90, inhibiting the E3 ligase complex CDL4DCAF12. We hypothesized that biallelic NF2 inactivation would be vulnerable to augmentation of CRL4DCAF12 through inhibition of CDK7. Methods: 50 Patients (the MEDUSA cohort) undergoing routine extended pleurectomy decortications consented to have multiregional sampling of their mesotheliomas at resection at 4-5 stereotyped locations, followed by multiregional whole exome sequencing (mWES 200x), phylogenetic deconvolution and transfer learning to examine evolutionary trajectories. Bulk RNA sequencing enabled gene set enrichment analysis, and spatial YAP phenotyping using tissue microarrays were conducted on the mWES profiled cohort. Primary cell lines were generated from a subset of mesotheliomas and whole exome sequenced. Results: NF2 exhibited biallelic inactivation involving copy number/mutation allelic heterogeneity in 42% of mesotheliomas. Double hits were predominantly clonal. Hippo signalosome exhibited additional clonal somatic alterations in 26% of mesotheliomas, with biallelic inactivation being observed in LATS2 (8%) and LATS1 (4%). Transfer learning identified NF2 inactivation as a predominantly secondary clonal event, constituting an evolutionary bottleneck. Random forest analysis revealed YAP dependent transcription, epithelial mesenchymal transition and spindle checkpoint transcriptional signature enrichments in NF2 double hit mesotheliomas. We conducted drug screening of NF2 wild type versus inactivated primary mesothelioma cell lines, which revealed selective sensitivity to CDK7 inhibitors THZ1 and YKL-5-124 in NF2 inactivated but not wild type MEDUSA cell lines. Conclusions: NF2 biallelic inactivation constitutes an evolutionary bottleneck during early mesothelioma evolution, associated with a specific vulnerability to CDK7 highlighting a potential path to clinical stratified therapy. Citation Format: Essa Y. Baitei, Min Zhang, Qianqian Sun, Jin-Li Luo, Philip Zhang, Tamihiro Kamata, James Harber, Aleksandra Bzura, Peter W. Jordan, Charlotte Poile, Alan Dawson, Apostolos Nakas, Cathy Richards, Hongji Yang, Ed Hollox, Dean A. Fennell. Clonal biallelic inactivation of NF2 is an evolutionary bottleneck that exposes a vulnerability to CDK7 inhibition in mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6086.
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Asimomitis, George, André G. Deslauriers, Andriana G. Kotini, Elsa Bernard, Davide Esposito, Malgorzata Olszewska, Nikolaos Spyrou, et al. "Isogenic MDS-RS Patient-Derived iPSCs Define the Mis-Spliced Transcript Repertoire and Chromatin Landscape of SF3B1-Mutant Hematopoietic Stem/Progenitor Cells." Blood 138, Supplement 1 (November 5, 2021): 147. http://dx.doi.org/10.1182/blood-2021-149830.
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Abstract The somatic hotspot mutation SF3B1K700E is characteristically found in myelodysplastic syndrome with ring sideroblasts (MDS-RS) and frequently occurs as an isolated mutation. However, our understanding of how this mutation drives MDS pathogenesis remains limited. To explore the downstream consequences of the SF3B1K700E mutation and its role in disease pathogenesis, we generated a panel of isogenic SF3B1K700E and SF3B1WT induced pluripotent stem cell (iPSC) lines from 3 MDS-RS patients with isolated SF3B1K700E mutation (3 SF3B1K700E and 3 SF3B1WT lines per patient, total 18). Upon hematopoietic differentiation, SF3B1K700E cells exhibited lower growth and colony-forming ability, compared to SF3B1WTcells, recapitulating hallmark phenotypes of MDS cells. To investigate the effects of the SF3B1K700E mutation on the transcriptome and chromatin landscape, we performed RNA- and ATAC- sequencing in purified CD34+/CD45+ hematopoietic stem/progenitor cells (HSPCs) derived from the panel of the 18 isogenic SF3B1K700E and SF3B1WT iPSC lines. Principal component analysis (PCA) and hierarchical clustering based on gene expression grouped the iPSC lines primarily by genotype (SF3B1K700E vs SF3B1WT) and secondarily by genetic background. To assess the impact of the SF3B1K700E mutation at the exon, transcript and gene level, we developed an analytical framework integrating differential splicing with differential transcript usage and differential gene expression analyses. We thus discovered 59 splicing events linked to 34 genes (most statistically significant events that also mapped to differentially used transcripts and differentially expressed genes). This SF3B1K700E splicing signature includes genes previously reported as mis-spliced in SF3B1K700E cells (e.g BRD9, ABCB7), as well as novel genes. We tested this signature against a published dataset of primary MDS patient samples (Pellagatti et al.). PCA based on the inclusion level of the splicing events of our signature separated SF3B1-mutated MDS patients from patients without splicing factor mutations (SF-WT) or healthy individuals. Furthermore, it identified one patient erroneously annotated as SF-WT that clustered together with the SF3B1-mutated patients, who had a, previously overlooked, 6bp in-frame deletion spanning the K700E hotspot. By comparing the chromatin accessibility profiles of SF3B1K700E and SF3B1WT iPSC-HSPCs to those defined in primary human cell types along the hematopoietic hierarchy (Corces et al.), we found that the chromatin landscape of SF3B1K700E HSPCs resembled more this of megakaryocyte-erythroid progenitor cells (MEPs) and erythroid cells, whereas that of SF3B1WT HSPCs resembled more granulocyte-monocyte progenitors (GMPs) and monocytes. This finding may underlie the more prominent involvement of the erythroid lineage in the pathology and clinical presentation of MDS-RS. To interrogate transcriptional programs in SF3B1K700E mutant cells, we performed transcription factor (TF) motif enrichment analysis. Motifs enriched in ATAC-Seq peaks more accessible in SF3B1K700E cells that were linked to genes upregulated in SF3B1K700E cells, included motifs of several TFs with known roles in hematopoiesis (GATA, ETS, STAT, AP-1). Unexpectedly, motifs of the TEAD TFs were also enriched. The TEAD family of TFs are best known as effectors of the Hippo signaling pathway, with important roles in various biological processes and malignancies, albeit no clear links to adult hematopoiesis or hematologic disease. TEAD2 and TEAD4 were upregulated in SF3B1-mutant, compared to the WT, iPSC-HSPCs and TEAD transcriptional activity, measured with a luciferase reporter construct, was higher in SF3B1K700E, compared to SF3B1WTiPSC-HSPCs. We did not find expression or activation of YAP or TAZ, which bind to DNA as a complex with TEAD upon Hippo pathway activation. These results support a Hippo-independent increase of TEAD expression and activity in SF3B1K700E cells. In summary, we generated a panel of isogenic patient-derived iPSCs that allowed us to comprehensively characterize the transcriptome and chromatin landscape of SF3B1K700E HSPCs in an isogenic system, derive a splicing signature of SF3B1K700E and identify the TEAD TF as a new transcriptional regulator of SF3B1K700Emutant HSPCs. G. Asimomitis, A.G. Deslauriers: shared 1 st authorship E. Papaemmanuil, E.P. Papapetrou: shared senior authorship Disclosures Deslauriers: Novo Nordisk A/S: Current Employment. Hellström-Lindberg: Celgene: Research Funding. Papaemmanuil: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months; Kyowa Hakko Kirin Pharma: Consultancy.
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Gao, Yunan, Yan Sun, Adife Gulhan Ercan-Sencicek, Justin S. King, Brynn N. Akerberg, Qing Ma, Maria I. Kontaridis, William T. Pu, and Zhiqiang Lin. "YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes." International Journal of Molecular Sciences 22, no. 13 (June 22, 2021): 6649. http://dx.doi.org/10.3390/ijms22136649.
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Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed. This study examined the expression pattern of Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, Tlr8, and Tlr9 in normal and disease-stressed mouse hearts. Our results demonstrated that the expression levels of cardiac Tlr3, Tlr7, Tlr8, and Tlr9 increased with age between neonatal and adult developmental stages, whereas the expression of Tlr5 decreased with age. Furthermore, pathological stress increased the expression levels of Tlr2, Tlr4, Tlr5, Tlr7, Tlr8, and Tlr9. Hippo-YAP signaling is essential for heart development and homeostasis maintenance, and YAP/TEAD1 complex is the terminal effector of this pathway. Here we found that TEAD1 directly bound genomic regions adjacent to Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, and Tlr9. In vitro, luciferase reporter data suggest that YAP/TEAD1 repression of Tlr4 depends on a conserved TEAD1 binding motif near Tlr4 transcription start site. In vivo, cardiomyocyte-specific YAP depletion increased the expression of most examined TLR genes, activated the synthesis of pro-inflammatory cytokines, and predisposed the heart to lipopolysaccharide stress. In conclusion, our data indicate that the expression of cardiac TLR genes is associated with age and activated by pathological stress and suggest that YAP/TEAD1 complex is a default repressor of cardiac TLR genes.
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Kadamb, Rama, Melisa Lopez Anton, Vivian Chua, Timothy Purwin, Maria Angelo Nieto Toledano, Andrew Aplin, and Julio Aguirre-Ghiso. "Abstract A009: NR2F1 inhibits Gaq/11-YAP-TAZ signaling and limits reactivation of uveal melanoma disseminated cancer cells via induction of dormancy." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): A009. http://dx.doi.org/10.1158/1538-7445.metastasis22-a009.
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Abstract Introduction: At the time of diagnosis, less than 5% of uveal melanoma (UM) patients have evidence of metastasis. However, up to 50% of UM patients will succumb to advanced metastatic in liver. UM cancer cells can persist undetected in liver for prolonged periods mainly and often take years-to-decades to grow out and do so without recurrence at the primary site. However, the mechanisms underlying the prolonged dormancy and why the liver is a preferred site for survival and eventual regrowth are a long-standing medical mystery. Results: GNAQ/11 are the main driving mutations in UM that activate downstream oncogenic YAP signaling. Using Gaq/11mut /BAPwt human uveal melanoma lines, we reveal that NR2F1, a neural cell commitment regulator is the main driver of regulating dormancy program. RNA-seq of rare UM disseminated cancer cells (DCCs) in livers identified that dormant DCCs upregulate the expression of neural differentiation genes, including NR2F1, while silencing Gaq downstream YAP/TAZ and cell cycle gene expression compared to proliferative cell clusters. Targeted pharmacological inhibition of Gaq/11mut signaling using YM-254890, an inhibitor of Gaq/11 resulted in NR2F1 upregulation and robust UM growth arrest. In contrast, inhibition of NR2F1 either by siRNA or CRISPR/cas9 upregulated YAP1 and its downstream targets at both transcript and protein levels along with increased colony growth in 3D culture. Importantly, UM solitary DCCs in nude mouse upregulated NR2F1 and in vivo CRISPR KO of NR2F1 results in dormant UM DCC awakening and massive metastatic growth in the murine liver. Immunofluorescence of UM patients’ liver metastatic lesions showed high expression of NR2F1 in solitary DCCs compared to the tumor mass. Chromatin-immunoprecipitation assays revealed that NR2F1 binds to the YAP1 promoter and regulates its gene expression. OMM1.3 CRISPR/Cas9 KO of NR2F1 cells showed increased recruitment of H3K4me3 and H3K27ac histone marks onto the YAP1 promoter while overexpression of NR2F1 decreased the recruitment of histone activating marks. Co-immunoprecipitation assay showed increased YAP1-TEAD1 complex formation in NR2F1 KO OMM1.3 cells while overexpression of NR2F1 reduced the abundance of this complex. Summary: Our work suggests that NR2F1 is required to maintain the single cell state of UM cells in the liver by inhibiting the YAP signally pathway. This study provides insight into the previously unrecognized mechanism of uveal melanoma dormancy opening a new space to design anti-metastatic therapies for UM patients. Citation Format: Rama Kadamb, Melisa Lopez Anton, Vivian Chua, Timothy Purwin, Maria Angelo Nieto Toledano, Andrew Aplin, Julio Aguirre-Ghiso. NR2F1 inhibits Gaq/11-YAP-TAZ signaling and limits reactivation of uveal melanoma disseminated cancer cells via induction of dormancy [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A009.
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Mougel, G., G. Mondielli, R. Appay, A. Querdray, C. Roche, A. Jijon, I. Konstantinova, A. Soude, T. Graillon, and A. Barlier. "P18.07.A Hippo signaling pathway is strongly involved in meningioma tumorigenesis." Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii95. http://dx.doi.org/10.1093/neuonc/noac174.334.
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Abstract Background Recurrent and aggressive meningiomas remain an unmet medical need in neuro-oncology. In mammals, Hippo signaling pathway is responsible for the growth of organs by regulating cell proliferation and apoptosis. The tumor suppressor NF2 protein belongs to the core of the Hippo pathway and a defect of its gene is present in 50% of meningiomas. Absence of NF2 keeps Hippo pathway inactive allowing the translocation of YAP/TAZ to the nucleus and the formation of a complex with TEADs. This complex then promotes the transcription of anti-apoptotic and proliferative genes such as CTGF, CYR61 and AXL. Here we present experimental results on human meningioma fragments and primary cell cultures supporting that Hippo pathway plays a critical role in meningioma tumorigenesis. Material and Methods The role of the Hippo pathway was studied on 57 meningiomas, well characterized at clinical, histological and molecular level. The genomic profile, target transcripts of the complex YAP/TAZ-TEADs, cell viability, and cell proliferation were analyzed after siRNA transfection targeting YAP, TAZ, YAP+TAZ and TEADs. Results Fifty-seven meningiomas were randomly selected including 27 WHO grade II and III tumors. Thirty (53%) presented a defect on the NF2 gene (NF2def) including 19(65%) grade II/III. NF2def meningiomas presented a significant increase of expression levels of Hippo pathway target transcripts CTGF, CYR61 and AXL in comparison with NF2 wild-type tumors (p<0.0001, p=0.0072 and p=0.0191, respectively). This increase was not correlated with the grade, the sex or with the cerebral localization of the meningiomas. On the other side, IHC analysis suggested this increase was correlated with the nuclear localization of YAP. Disturbing the YAP/TAZ-TEADs complex using siRNA on 10 meningiomas (5 NF2 wild-type and 5 NF2 def) induced a significant decrease on cell proliferation but not on cell viability. This decrease was more important when TAZ was turned off in comparison to turning off of YAP. Conclusion Our experimental results strongly support the importance of the Hippo pathway in meningioma tumorigenesis, supporting its relevance as a new target in meningioma therapy. A.Barlier reports receiving research grants from Inventiva Pharma. No potential conflicts of interest were disclosed by the other authors.
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Song, Yong, Jing Fu, Min Zhou, Li Xiao, Xue Feng, Hengxi Chen, and Wei Huang. "Activated Hippo/Yes-Associated Protein Pathway Promotes Cell Proliferation and Anti-apoptosis in Endometrial Stromal Cells of Endometriosis." Journal of Clinical Endocrinology & Metabolism 101, no. 4 (April 1, 2016): 1552–61. http://dx.doi.org/10.1210/jc.2016-1120.
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Abstract Context: The imbalance in cell proliferation and apoptosis is considered an important role in the pathogenesis of endometriosis, but the exact mechanisms remains unclear. A newly established signaling pathway–Hippo/Yes-associated protein (YAP) pathway plays a critical role in the proliferation and apoptosis processes. However, studies focusing on Hippo/YAP pathway and endometriosis are lacking. Objective: The objective was to explore the function of the Hippo/YAP pathway in endometriosis. Setting and Design: The expression of YAP was first investigated in endometrium of women with or without endometriosis. The role of YAP in cell proliferation and apoptosis is identified by transfection of endometrial stromal cells (ESCs) in vitro, subsequent Verteporfin treatments in eutopic ESCs in vitro, and endometriosis animal model of nude mice in vivo. Results: Our results revealed that increased expression of YAP and decreased expression of p-YAP in ectopic and eutopic endometrium compared with normal endometrium. YAP knockdown in eutopic ESCs decreased cell proliferation and enhanced cell apoptosis companied with decreased expression of TEAD1, CTGF, and B-cell lymphoma/leukemia (BCL)-2; whereas overexpression of YAP resulted in increased proliferation and decreased apoptosis of normal ESCs with increased expression of TEAD1, CTGF, and BCL-2. By chromatin immunoprecipitation qPCR CTGF and BCL-2 were identified as directly downstream target genes of YAP-TEAD1 active complex. Eutopic ESCs treated with Verteporfin revealed decreased proliferation and enhanced apoptosis whereas in endometriosis animal models of nude mice treated with Verteporfin, the size of endometriotic lesions was significantly reduced. Conclusions: Our study suggests that the Hippo/YAP-signaling pathway plays a critical role in the pathogenesis of endometriosis and should present a novel therapeutic method against endometriosis.
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Eisinger-Mathason, T. S. Karin, Vera Mucaj, Kevin M. Biju, Michael S. Nakazawa, Mercy Gohil, Timothy P. Cash, Sam S. Yoon, et al. "Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis." Proceedings of the National Academy of Sciences 112, no. 26 (June 15, 2015): E3402—E3411. http://dx.doi.org/10.1073/pnas.1420005112.
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Genetic aberrations responsible for soft-tissue sarcoma formation in adults are largely unknown, with targeted therapies sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft-tissue sarcomas, resulting in elevated expression of the effector molecule Yes-Associated Protein (YAP). Based on data gathered from human sarcoma patients, a novel autochthonous mouse model, and mechanistic analyses, we determined that YAP-dependent expression of the transcription factor forkhead box M1 (FOXM1) is necessary for cell proliferation/tumorigenesis in a subset of soft-tissue sarcomas. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in coregulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of some sarcoma subtypes.