Статті в журналах: "Forkhead box protein A1"

1

Jain, Rohit K., Rutika J. Mehta, Harikrishna Nakshatri, Muhammad T. Idrees, and Sunil S. Badve. "High-level expression of forkhead-box protein A1 in metastatic prostate cancer." Histopathology 58, no. 5 (March 14, 2011): 766–72. http://dx.doi.org/10.1111/j.1365-2559.2011.03796.x.

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HE, KELI, HUI ZENG, XIANQUN XU, ANLING LI, QING CAI, and XINGHUA LONG. "Clinicopathological significance of forkhead box protein A1 in breast cancer: A meta-analysis." Experimental and Therapeutic Medicine 11, no. 6 (April 6, 2016): 2525–30. http://dx.doi.org/10.3892/etm.2016.3229.

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3

Ma, Wenqi, Jue Jiang, Miao Li, Hua Wang, Hongli Zhang, Xin He, Lili Huang, and Qi Zhou. "The clinical significance of forkhead box protein A1 and its role in colorectal cancer." Molecular Medicine Reports 14, no. 3 (August 1, 2016): 2625–31. http://dx.doi.org/10.3892/mmr.2016.5583.

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4

Gayyed, MarianaF, MagdyF Ahmed, MedhatM Soliman, and Maram El-Hussieny. "Expression and prognostic significance of caveolin-1 and forkhead box protein A1 in gastric adenocarcinoma." Egyptian Journal of Pathology 40, no. 2 (2020): 162. http://dx.doi.org/10.4103/egjp.egjp_2_21.

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5

Hu, Dong Gui, and Peter I. Mackenzie. "Forkhead Box Protein A1 Regulates UDP-Glucuronosyltransferase 2B15 Gene Transcription in LNCaP Prostate Cancer Cells." Drug Metabolism and Disposition 38, no. 12 (August 24, 2010): 2105–9. http://dx.doi.org/10.1124/dmd.110.035436.

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6

Song, Lan, Zhaojun Xu, Ling Li, Mei Hu, Lijuan Cheng, Lingli Chen, and Bo Zhang. "Forkhead box protein A1 inhibits the expression of uncoupling protein 2 in hydrogen peroxide-induced A549 cell line." Cell Stress and Chaperones 19, no. 1 (April 28, 2013): 53–60. http://dx.doi.org/10.1007/s12192-013-0433-z.

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7

Ren, Hongyu, Pei Zhang, Yong Tang, Mengping Wu, and Weikang Zhang. "Forkhead Box Protein A1 is a Prognostic Predictor and Promotes Tumor Growth of Gastric Cancer [Retraction]." OncoTargets and Therapy Volume 15 (July 2022): 829–30. http://dx.doi.org/10.2147/ott.s383786.

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8

Liu, Jian, Bohua Chen, Bin Yue, and Junde Yang. "MicroRNA-212 suppresses the proliferation and migration of osteosarcoma cells by targeting forkhead box protein A1." Experimental and Therapeutic Medicine 12, no. 6 (November 7, 2016): 4135–41. http://dx.doi.org/10.3892/etm.2016.3880.

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9

Wang, Shixiong, Sachin Singh, Madhumohan Katika, Sandra Lopez-Aviles, and Antoni Hurtado. "High Throughput Chemical Screening Reveals Multiple Regulatory Proteins on FOXA1 in Breast Cancer Cell Lines." International Journal of Molecular Sciences 19, no. 12 (December 19, 2018): 4123. http://dx.doi.org/10.3390/ijms19124123.

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Forkhead box A1 (FOXA1) belongs to the forkhead class transcription factor family, playing pioneering function for hormone receptors in breast and prostate cancers, and mediating activation of linage specific enhancers. Interplay between FOXA1 and breast cancer specific signaling pathways has been reported previously, indicating a regulation network on FOXA1 in breast cancer cells. Here in this study, we aimed to identify which are the proteins that could potentially control FOXA1 function in breast cancer cell lines expressing different molecular markers. We first established a luciferase reporter system reflecting FOXA1 binding to DNA. Then, we applied high throughput chemical screening of multiple protein targets and mass spectrometry in breast cancer cell lines expressing different molecular markers: ER positive/HER2 negative (MCF-7), ER positive/HER2 positive (BT474), and ER negative/HER2 positive (MDA-MB-453). Regardless of estrogen receptor status, HER2 (human epidermal growth factor receptor 2) enriched cell lines showed similar response to kinase inhibitors, indicating the control of FOXA1 by cell signaling kinases. Among these kinases, we identified additional receptor tyrosine kinases and cyclin-dependent kinases as regulators of FOXA1. Furthermore, we performed proteomics experiments from FOXA1 inmunoprecipitated protein complex to identify that FOXA1 interacts with several proteins. Among all the targets, we identified cyclin-dependent kinase 1 (CDK1) as a positive factor to interact with FOXA1 in BT474 cell line. In silico analyses confirmed that cyclin-dependent kinases might be the kinases responsible for FOXA1 phosphorylation at the Forkhead domain and the transactivation domain. These results reveal that FOXA1 is potentially regulated by multiple kinases. The cell cycle control kinase CDK1 might control directly FOXA1 by phosphorylation and other kinases indirectly by means of regulating other proteins.

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10

Wang, Li-Li, Yin-Ling Xiu, Xi Chen, Kai-Xuan Sun, Shuo Chen, Dan-Dan Wu, Bo-Liang Liu, and Yang Zhao. "The transcription factor FOXA1 induces epithelial ovarian cancer tumorigenesis and progression." Tumor Biology 39, no. 5 (May 2017): 101042831770621. http://dx.doi.org/10.1177/1010428317706210.

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FOXA1 (forkhead box A1), a member of the FOXA transcription factor superfamily, plays an important role in tumor occurrence and development. However, the relationship between FOXA1 and ovarian cancer has not been reported. We examined normal ovarian tissue and ovarian cancer tissue and found increased FOXA1 expression in the cancer tissue. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and flow cytometry assays demonstrated that transfection with small interfering RNA to silence FOXA1 (si-FOXA1) in ovarian cancer cell lines decreased cell proliferation and induced apoptosis and S-phase arrest. In addition, si-FOXA1 transfection inhibited cell migration and invasion. Western blotting showed that si-FOXA1 transfection decreased the levels of YY1-associated protein 1, cyclin-dependent kinase 1, cyclin D1, phosphatidylinositol-3 kinase, E2F transcription factor 1, B-cell lymphoma 2, and vascular endothelial growth factor A protein. Based on these results, we suggest that FOXA1 plays a catalytic role in ovarian cancer pathogenesis and development by affecting the expression of the above-mentioned proteins.

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11

Park, Su H., Ka-wing Fong, Jung Kim, Fang Wang, Xiaodong Lu, Yongik Lee, Lourdes T. Brea, et al. "Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer." Science Advances 7, no. 15 (April 2021): eabe2261. http://dx.doi.org/10.1126/sciadv.abe2261.

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Forkhead box protein A1 (FOXA1) is essential for androgen-dependent prostate cancer (PCa) growth. However, how FOXA1 levels are regulated remains elusive and its therapeutic targeting proven challenging. Here, we report FOXA1 as a nonhistone substrate of enhancer of zeste homolog 2 (EZH2), which methylates FOXA1 at lysine-295. This methylation is recognized by WD40 repeat protein BUB3, which subsequently recruits ubiquitin-specific protease 7 (USP7) to remove ubiquitination and enhance FOXA1 protein stability. They functionally converge in regulating cell cycle genes and promoting PCa growth. FOXA1 is a major therapeutic target of the inhibitors of EZH2 methyltransferase activities in PCa. FOXA1-driven PCa growth can be effectively mitigated by EZH2 enzymatic inhibitors, either alone or in combination with USP7 inhibitors. Together, our study reports EZH2-catalyzed methylation as a key mechanism to FOXA1 protein stability, which may be leveraged to enhance therapeutic targeting of PCa using enzymatic EZH2 inhibitors.

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12

Tokunaga, E., Y. Hisamatsu, S. Okada, N. Yamashita, Y. Nakashima, H. Saeki, Y. Emi, M. Morita, Y. Kakeji, and Y. Maehara. "Expression of forkhead-box protein A1 (FOXA1) as a significant prognostic and predictive marker for ER-positive breast cancer." Journal of Clinical Oncology 28, no. 15_suppl (May 20, 2010): 608. http://dx.doi.org/10.1200/jco.2010.28.15_suppl.608.

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13

Ma, Yunyan, LV Xiaoyan, Xiaojiang Jia, Jingzhen Zhou, Zhenbo Ouyang, Zhen Gao, Wenjuan Qiao, Xin Liu, and Ninghu Zhu. "The Role and Mechanism of Human Papillomavirus16 E7 (HPV16 E7) in the Proliferation and Invasion of Cervical Cancer Cells Through Regulating Forkhead Box Protein A1." Journal of Biomaterials and Tissue Engineering 10, no. 8 (August 1, 2020): 1206–12. http://dx.doi.org/10.1166/jbt.2020.2481.

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High-risk HPV16 is an important factor for cervical cancer. HPV16 E7 can promote the malignant transformation of cervical epithelial cells. Forkhead box protein A1 (FOXA1) is abnormally expressed in several tumors. Our study assessed HPV16 E7's effect on cervical cancer cells. Hela cells were divided into control group; HPV16 E7 group; and siFOXA1+ HPV16 E7 group followed by analysis of HPV16 E7 and FOXA1 expression by Real-time PCR and Western blot, cell proliferation by MTT assay, Caspase 3 activity, Bax and Bcl-2 expression by Real-time PCR as well as cell invasion by Transwell assay. In HPV16 E7 group, HPV16 E7 and HOXA1 expression was significantly increased, cell proliferation was promoted, invasive ability was increased, Caspase 3 activity and Bax expression was decreased, and Bcl-2 expression was increased compared to control group (P < 0 05). Conversely, inhibition of FOXA1 expression in Hela cells overexpressing HPV16 E7 can significantly inhibit cell proliferation and invasion, and promote apoptosis (P < 0 05). HPV16 E7 protein can up-regulate FOXA1 in host cells, and promote cervical cancer cell growth, proliferation and invasion, indicating that it is one of the key factors contributing to cervical cancer.

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14

Aung, Khin Moh Moh, Siu Yee New, Shuzhen Hong, Laura Sutarlie, Michelle Gek Liang Lim, Si Kee Tan, Edwin Cheung, and Xiaodi Su. "Studying forkhead box protein A1–DNA interaction and ligand inhibition using gold nanoparticles, electrophoretic mobility shift assay, and fluorescence anisotropy." Analytical Biochemistry 448 (March 2014): 95–104. http://dx.doi.org/10.1016/j.ab.2013.11.017.

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15

Fu, Xiaoyong, Rinath Jeselsohn, Resel Pereira, Emporia F. Hollingsworth, Chad J. Creighton, Fugen Li, Martin Shea, et al. "FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer." Proceedings of the National Academy of Sciences 113, no. 43 (October 6, 2016): E6600—E6609. http://dx.doi.org/10.1073/pnas.1612835113.

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Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)–chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors.

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16

Ademuyiwa, Foluso O., Mangesh A. Thorat, Rohit K. Jain, Harikrishna Nakshatri, and Sunil Badve. "Expression of Forkhead-box protein A1, a marker of luminal A type breast cancer, parallels low Oncotype DX 21-gene recurrence scores." Modern Pathology 23, no. 2 (November 27, 2009): 270–75. http://dx.doi.org/10.1038/modpathol.2009.172.

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17

Zhang, Gaihua, Yongbing Zhao, Yi Liu, Li-Pin Kao, Xiao Wang, Benjamin Skerry, and Zhaoyu Li. "FOXA1 defines cancer cell specificity." Science Advances 2, no. 3 (March 2016): e1501473. http://dx.doi.org/10.1126/sciadv.1501473.

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A transcription factor functions differentially and/or identically in multiple cell types. However, the mechanism for cell-specific regulation of a transcription factor remains to be elucidated. We address how a single transcription factor, forkhead box protein A1 (FOXA1), forms cell-specific genomic signatures and differentially regulates gene expression in four human cancer cell lines (HepG2, LNCaP, MCF7, and T47D). FOXA1 is a pioneer transcription factor in organogenesis and cancer progression. Genomewide mapping of FOXA1 by chromatin immunoprecipitation sequencing annotates that target genes associated with FOXA1 binding are mostly common to these cancer cells. However, most of the functional FOXA1 target genes are specific to each cancer cell type. Further investigations using CRISPR-Cas9 genome editing technology indicate that cell-specific FOXA1 regulation is attributable to unique FOXA1 binding, genetic variations, and/or potential epigenetic regulation. Thus, FOXA1 controls the specificity of cancer cell types. We raise a “flower-blooming” hypothesis for cell-specific transcriptional regulation based on these observations.

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18

Pan, Jie, Zongbin Xu, Meifang Xu, Xiaoyan Lin, Bingqiang Lin, and Mengxin Lin. "Knockdown of Forkhead box A1 suppresses the tumorigenesis and progression of human colon cancer cells through regulating the phosphatase and tensin homolog/Akt pathway." Journal of International Medical Research 48, no. 12 (December 2020): 030006052097145. http://dx.doi.org/10.1177/0300060520971453.

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Background This study aimed to evaluate the role and the underlying mechanisms of Forkhead box A1 (encoded by FOXA1) in colon cancer. Methods We analyzed FOXA1 mRNA and protein expression in colon cancer tissues and cell lines. We also silenced FOXA1 expression in HCT116 and SW480 cells to evaluate the effects on cell proliferation, cell cycle, migration, and invasion by using MTT, colony formation, flow cytometry, and the Transwell assay, respectively. Results FOXA1 immunostaining was higher in colon cancer tissues than adjacent healthy tissues. FOXA1 mRNA and protein expression was significantly increased in human colon cancer cells compared with a normal colonic cell line. FOXA1 expression was also significantly higher in colorectal cancer tissues from TCGA data sets and was associated with worse prognosis in the R2 database. FOXA1 expression was negatively correlated with the extent of its methylation, and its knockdown reduced proliferation, migration, and invasion, and induced G2/M phase arrest in HCT116 and SW480 cells by suppressing the phosphatase and tensin homolog/Akt signaling pathway and inhibiting epithelial–mesenchymal transition. Conclusion FOXA1 may act as an oncogene in colon cancer tumorigenesis and development.

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19

Hirata, Kensuke, Yuki Takakura, Misato Shibazaki, Mariko Morii, Takuya Honda, Motohiko Oshima, Kazumasa Aoyama та ін. "Forkhead box protein A1 confers resistance to transforming growth factor‐β‐induced apoptosis in breast cancer cells through inhibition of Smad3 nuclear translocation". Journal of Cellular Biochemistry 120, № 2 (11 вересня 2018): 2259–70. http://dx.doi.org/10.1002/jcb.27551.

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20

Wang, Ying, Yang Zhang, Huimin Wang, Junxiao Wang, Yiyuan Zhang, Yingzhe Wang, Zhenwei Pan, and Shanshun Luo. "Aberrantly Up-regulated miR-20a in Pre-eclampsic Placenta Compromised the Proliferative and Invasive Behaviors of Trophoblast Cells by Targeting Forkhead Box Protein A1." International Journal of Biological Sciences 10, no. 9 (2014): 973–82. http://dx.doi.org/10.7150/ijbs.9088.

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21

Zhu, Xuchao, Dan Li, Fei Yu, Chengyou Jia, Jing Xie, Yushui Ma, Suyun Fan, et al. "miR-194 inhibits the proliferation, invasion, migration, and enhances the chemosensitivity of non-small cell lung cancer cells by targeting forkhead box A1 protein." Oncotarget 7, no. 11 (February 21, 2016): 13139–52. http://dx.doi.org/10.18632/oncotarget.7545.

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22

Endo, Yumi, Tatsuya Toyama, Satoru Takahashi, Nobuyasu Yoshimoto, Mai Iwasa, Tomoko Asano, Yoshitaka Fujii та Hiroko Yamashita. "Association of MiR-1290 and its potential targets with characteristics of estrogen receptor α-positive breast cancer." Journal of Clinical Oncology 31, № 15_suppl (20 травня 2013): 614. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.614.

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614 Background: Recent analyses have identified heterogeneity in estrogen receptor (ER) α-positive breast cancer. Subtypes called luminal A and luminal B have been identified, and the tumor characteristics, such as response to endocrine therapy and prognosis are different in these subtypes. However, little is known about how the biological characteristics of ER-positive breast cancer are determined. Methods: In this study, expression profiles of microRNAs (miRNAs) and mRNAs in ER-positive breast cancer tissue were compared between ERhigh Ki67low tumors and ERlow Ki67hightumors by miRNA and mRNA microarrays. Results: Unsupervised hierarchical clustering analyses revealed distinct expression patterns of miRNAs and mRNAs. We identified a down-regulation of miR-1290 and up-regulations of 6 miRNAs in ERhigh Ki67lowtumors. We picked up 11 genes that were potential target genes of the selected miRNAs. Protein expression patterns of the selected target genes were analyzed in ER-positive breast cancer samples by immunohistochemistry: miR-1290 and its 4 putative targets, BCL2, forkhead box A1 (FOXA1), microtubule associated protein tau (MAPT) and N-acetyltransferase-1 (NAT1) were identified. Transfection experiments revealed that introduction of miR-1290 into ER-positive breast cancer cells decreased mRNA and protein expression of NAT1 and FOXA1. Conclusions: Our results suggest that miR-1290 and its potential targets, NAT1 and FOXA1, might be associated with characteristics of ER-positive breast cancer.

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23

Yamaguchi, Noritaka, Yuji Nakayama, and Naoto Yamaguchi. "Down-regulation of Forkhead box protein A1 (FOXA1) leads to cancer stem cell-like properties in tamoxifen-resistant breast cancer cells through induction of interleukin-6." Journal of Biological Chemistry 292, no. 20 (March 7, 2017): 8136–48. http://dx.doi.org/10.1074/jbc.m116.763276.

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24

Hamdi, Yosr, Martin Leclerc, Martine Dumont, Stéphane Dubois, Martine Tranchant, Guy Reimnitz, Penny Soucy, et al. "Functional Analysis of Promoter Variants in Genes Involved in Sex Steroid Action, DNA Repair and Cell Cycle Control." Genes 10, no. 3 (February 28, 2019): 186. http://dx.doi.org/10.3390/genes10030186.

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Genetic variants affecting the regulation of gene expression are among the main causes of human diversity. The potential importance of regulatory polymorphisms is underscored by results from Genome Wide Association Studies, which have already implicated such polymorphisms in the susceptibility to complex diseases such as breast cancer. In this study, we re-sequenced the promoter regions of 24 genes involved in pathways related to breast cancer including sex steroid action, DNA repair, and cell cycle control in 60 unrelated Caucasian individuals. We constructed haplotypes and assessed the functional impact of promoter variants using gene reporter assays and electrophoretic mobility shift assays. We identified putative functional variants within the promoter regions of estrogen receptor 1 (ESR1), ESR2, forkhead box A1 (FOXA1), ubiquitin interaction motif containing 1 (UIMC1) and cell division cycle 7 (CDC7). The functional polymorphism on CDC7, rs13447455, influences CDC7 transcriptional activity in an allele-specific manner and alters DNA–protein complex formation in breast cancer cell lines. Moreover, results from the Breast Cancer Association Consortium show a marginal association between rs13447455 and breast cancer risk (p=9.3x10-5), thus warranting further investigation. Furthermore, our study has helped provide methodological solutions to some technical difficulties that were encountered with gene reporter assays, particularly regarding inter-clone variability and statistical consistency.

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25

Takayama, Ken-ichi, Takashi Suzuki, Shuichi Tsutsumi, Tetsuya Fujimura, Satoru Takahashi, Yukio Homma, Tomohiko Urano, Hiroyuki Aburatani, and Satoshi Inoue. "Integrative Analysis of FOXP1 Function Reveals a Tumor-Suppressive Effect in Prostate Cancer." Molecular Endocrinology 28, no. 12 (December 1, 2014): 2012–24. http://dx.doi.org/10.1210/me.2014-1171.

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The transcriptional network of the androgen receptor (AR), a key molecule of prostate cancer, is frequently modulated by interactions with other transcriptional factors such as forkhead box protein A1 (FOXA1). However, global regulatory mechanisms of AR signaling mediated by such factors have not been well investigated. Here we conducted a chromatin immunoprecipitation sequence analysis, which revealed that another FOX family, FOXP1, is specifically regulated by both AR and FOXA1. We also found that FOXP1 acts as a tumor suppressor in prostate cancer through inhibiting cell proliferation and migration. We generated an extensive global map of FOXP1 binding sites and found that FOXP1 is directly involved in AR-mediated transcription. We demonstrated that FOXP1 has a repressive effect on AR-induced transcriptional activity or histone modification in enhancer regions. Moreover, by a global analysis of androgen-mediated transcriptional networks, we observed enrichment of FOXP1 binding genes in the gene cluster negatively regulated by FOXP1. Evaluation of FOXP1 expression in clinical samples indicated that the decreased expression of FOXP1 is another prognostic factor of prostate cancer. Taken together, our results suggest a novel mechanism in which AR-induced FOXP1 functions as a direct modulator of the AR and FOXA1 centric global transcriptional network.

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Sutinen, Päivi, Vesa Rahkama, Miia Rytinki, and Jorma J. Palvimo. "Nuclear Mobility and Activity of FOXA1 with Androgen Receptor Are Regulated by SUMOylation." Molecular Endocrinology 28, no. 10 (October 1, 2014): 1719–28. http://dx.doi.org/10.1210/me.2014-1035.

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Forkhead box (FOX) protein A1 has been dubbed a pioneer transcription factor because it binds target sites in DNA, thereby displacing nucleosomes to loosen chromatin and facilitating steroid receptor DNA binding nearby. FOXA1 is an important regulator of prostate development, collaborating with androgen receptor (AR). Post-translational modifications regulating FOXA1 are thus far poorly understood. SUMOylation, post-translational modification of proteins by small ubiquitin-like modifier (SUMO) proteins, has emerged as an important regulatory mechanism in transcriptional regulation. In this work, we show by SUMOylation assays in COS-1 cells that the FOXA1 is modified at least in two of its three lysines embedded in SUMOylation consensus, K6 and K389, in proximity to its transactivation domains and K267 proximal to its DNA-binding domain. We also provide evidence for SUMO-2/3 modification of endogenous FOXA1 in LNCaP prostate cancer cells. Based on fluorescence recovery after photobleaching assays with mCherry-fused FOXA1 and EGFP-fused AR in HEK293 cells, the presence of FOXA1 retards the nuclear mobility of agonist-bound AR. Interestingly, mutation of the FOXA1 SUMOylation sites slows down the mobility of the pioneer factor, further retarding the nuclear mobility of the AR. Chromatin immunoprecipitation and gene expression assays suggest that the mutation enhances FOXA1's chromatin occupancy as well as its activity on AR-regulated prostate-specific antigen (PSA) locus in LNCaP cells. Moreover, the mutation altered the ability of FOXA1 to influence proliferation of LNCaP cells. Taken together, these results strongly suggest that the SUMOylation can regulate the transcriptional activity of FOXA1 with the AR.

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Chu, Yang, Linan Bao, Yun Teng, Bo Yuan, Lijie Ma, Ying Liu, and Hui Kang. "The Fibrotic Effects of LINC00663 in Human Hepatic Stellate LX-2 Cells and in Bile Duct-Ligated Cholestasis Mice Are Mediated through the Splicing Factor 2-Fibronectin." Cells 12, no. 2 (January 4, 2023): 215. http://dx.doi.org/10.3390/cells12020215.

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Hepatic fibrosis can develop into cirrhosis or even cancer without active therapy at an early stage. Long non-coding RNAs (lncRNAs) have been shown to be involved in the regulation of a wide variety of important biological processes. However, lncRNA mechanism(s) involved in cholestatic liver fibrosis remain unclear. RNA sequence data of hepatic stellate cells from bile duct ligation (BDL) mice or controls were analyzed by weighted gene co-expression network analysis (WGCNA). Based on WGCNA analysis, a competing endogenous RNA network was constructed. We identified LINC00663 and evaluated its function using a panel of assays, including a wound healing assay, a dual-luciferase reporter assay, RNA binding protein immunoprecipitation and chromatin immunoprecipitation. Functional research showed that LINC00663 promoted the activation, migration and epithelial–mesenchymal transition (EMT) of LX-2 cells and liver fibrosis in BDL mice. Mechanistically, LINC00663 regulated splicing factor 2 (SF2)-fibronectin (FN) alternative splicing through the sponging of hsa-miR-3916. Moreover, forkhead box A1 (FOXA1) specifically interacted with the promoter of LINC00663. In summary, we elaborated the fibrotic effects of LINC00663 in human hepatic stellate LX-2 cells and in bile duct-ligated cholestasis mice. We established a FOXA1/LINC00663/hsa-miR-3916/SF2-FN axis that provided a potential target for the diagnosis and targeted therapy of cholestatic liver fibrosis.

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Wang, Zhuo, Bao-Sheng Sun, Zhi-Shen Chen, Kang-Kang Zhao, Yun-Long Wang, Fan-Xu Meng, and Yang Zhang. "FOXA1 Leads to Aberrant Expression of SIX4 Affecting Cervical Cancer Cell Growth and Chemoresistance." Analytical Cellular Pathology 2022 (April 20, 2022): 1–18. http://dx.doi.org/10.1155/2022/9675466.

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Cervical cancer (CC) is among the most prevalent cancers among female populations with high recurrence rates all over the world. Cisplatin (DDP) is the first-line treatment for multiple cancers, including CC. The main problem associated with its clinical application is drug resistance. This study is aimed at investigating the function and downstream regulation mechanism of forkhead-box A1 (FOXA1) in CC, which was verified as an oncogene in several cancers. Using GEO database and bioinformatics analysis, we identified FOXA1 as a possible oncogene in CC. Silencing of FOXA1 inhibited CC cell growth, invasion, and chemoresistance. Afterwards, the downstream gene of FOXA1 was predicted using a bioinformatics website and validated using ChIP and dual-luciferase assays. SIX4, a possible target of FOXA1, promoted CC cell malignant aggressiveness and chemoresistance. In addition, overexpression of SIX4 promoted phosphorylation of PI3K and AKT proteins and activated the PI3K/AKT signaling pathway. Further overexpression of SIX4 reversed the repressive effects of FOXA1 knockdown on CC cell growth, invasion, and chemoresistance in DDP-resistant cells. FOXA1-induced SIX4 facilitates CC progression and chemoresistance, highlighting a strong potential for FOXA1 to serve as a promising therapeutic target in CC.

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He, Zihao, Xiaolu Duan, and Guohua Zeng. "Identification of potential biomarkers and pivotal biological pathways for prostate cancer using bioinformatics analysis methods." PeerJ 7 (October 4, 2019): e7872. http://dx.doi.org/10.7717/peerj.7872.

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Background Prostate cancer (PCa) is a common urinary malignancy, whose molecular mechanism has not been fully elucidated. We aimed to screen for key genes and biological pathways related to PCa using bioinformatics method. Methods Differentially expressed genes (DEGs) were filtered out from the GSE103512 dataset and subjected to the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The protein–protein interactions (PPI) network was constructed, following by the identification of hub genes. The results of former studies were compared with ours. The relative expression levels of hub genes were examined in The Cancer Genome Atlas (TCGA) and Oncomine public databases. The University of California Santa Cruz Xena online tools were used to study whether the expression of hub genes was correlated with the survival of PCa patients from TCGA cohorts. Results Totally, 252 (186 upregulated and 66 downregulated) DEGs were identified. GO analysis enriched mainly in “oxidation-reduction process” and “positive regulation of transcription from RNA polymerase II promoter”; KEGG pathway analysis enriched mostly in “metabolic pathways” and “protein digestion and absorption.” Kallikrein-related peptidase 3, cadherin 1 (CDH1), Kallikrein-related peptidase 2 (KLK2), forkhead box A1 (FOXA1), and epithelial cell adhesion molecule (EPCAM) were identified as hub genes from the PPI network. CDH1, FOXA1, and EPCAM were validated by other relevant gene expression omnibus datasets. All hub genes were validated by both TCGA and Oncomine except KLK2. Two additional top DEGs (ABCC4 and SLPI) were found to be associated with the prognosis of PCa patients. Conclusions This study excavated the key genes and pathways in PCa, which might be biomarkers for diagnosis, prognosis, and potential therapeutic targets.

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Gosalia, Nehal, Daniel Neems, Jenny L. Kerschner, Steven T. Kosak, and Ann Harris. "Architectural proteins CTCF and cohesin have distinct roles in modulating the higher order structure and expression of the CFTR locus." Nucleic Acids Research 42, no. 15 (July 31, 2014): 9612–22. http://dx.doi.org/10.1093/nar/gku648.

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Abstract Higher order chromatin structures across the genome are maintained in part by the architectural proteins CCCTC binding factor (CTCF) and the cohesin complex, which co-localize at many sites across the genome. Here, we examine the role of these proteins in mediating chromatin structure at the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR encompasses nearly 200 kb flanked by CTCF-binding enhancer-blocking insulator elements and is regulated by cell-type-specific intronic enhancers, which loop to the promoter in the active locus. SiRNA-mediated depletion of CTCF or the cohesin component, RAD21, showed that these two factors have distinct roles in regulating the higher order organization of CFTR. CTCF mediates the interactions between CTCF/cohesin binding sites, some of which have enhancer-blocking insulator activity. Cohesin shares this tethering role, but in addition stabilizes interactions between the promoter and cis-acting intronic elements including enhancers, which are also dependent on the forkhead box A1/A2 (FOXA1/A2) transcription factors (TFs). Disruption of the three-dimensional structure of the CFTR gene by depletion of CTCF or RAD21 increases gene expression, which is accompanied by alterations in histone modifications and TF occupancy across the locus, and causes internalization of the gene from the nuclear periphery.

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Erdős, Edina, and Bálint László Bálint. "NR2F2 Orphan Nuclear Receptor is Involved in Estrogen Receptor Alpha-Mediated Transcriptional Regulation in Luminal A Breast Cancer Cells." International Journal of Molecular Sciences 21, no. 6 (March 11, 2020): 1910. http://dx.doi.org/10.3390/ijms21061910.

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Nuclear Receptor Subfamily 2 Group F Member 2 (NR2F2) is a member of the steroid/thyroid hormone receptor superfamily with a crucial role in organogenesis, angiogenesis, cardiovascular development and tumorigenesis. However, there is limited knowledge about the cistrome and transcriptome of NR2F2 in breast cancer. In this study, we mapped the regulatory mechanism by NR2F2 using functional genomic methods. To investigate the clinical significance of NR2F2 in breast cancer, The Cancer Genome Atlas (TCGA) data were used. These results show that a high NR2F2 is associated with better survival of a specific subset of patients, namely those with luminal A breast cancer. Therefore, genome-wide NR2F2 and estrogen receptor alpha (ERα) binding sites were mapped in luminal A breast cancer cells using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq), revealing that most NR2F2 overlap with ERα that are co-occupied by forkhead box A1 (FOXA1) and GATA binding protein 3 (GATA3) in active enhancer regions. NR2F2 overlaps with highly frequent ERα chromatin interactions, which are essential for the formation of ERα-bound super-enhancers. In the process of the transcriptome profiling of NR2F2-depleted breast cancer cells such differentially expressed genes have been identified that are involved in endocrine therapy resistance and are also ERα target genes. Overall, these findings demonstrate that the NR2F2 nuclear receptor has a key role in ERα-mediated transcription and it can offer a potential therapeutic target in patients with luminal A breast cancer.

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Kerschner, Jenny L., and Ann Harris. "Transcriptional networks driving enhancer function in the CFTR gene." Biochemical Journal 446, no. 2 (August 14, 2012): 203–12. http://dx.doi.org/10.1042/bj20120693.

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A critical cis-regulatory element for the CFTR (cystic fibrosis transmembrane conductance regulator) gene is located in intron 11, 100 kb distal to the promoter, with which it interacts. This sequence contains an intestine-selective enhancer and associates with enhancer signature proteins, such as p300, in addition to tissue-specific TFs (transcription factors). In the present study we identify critical TFs that are recruited to this element and demonstrate their importance in regulating CFTR expression. In vitro DNase I footprinting and EMSAs (electrophoretic mobility-shift assays) identified four cell-type-selective regions that bound TFs in vitro. ChIP (chromatin immunoprecipitation) identified FOXA1/A2 (forkhead box A1/A2), HNF1 (hepatocyte nuclear factor 1) and CDX2 (caudal-type homeobox 2) as in vivo trans-interacting factors. Mutation of their binding sites in the intron 11 core compromised its enhancer activity when measured by reporter gene assay. Moreover, siRNA (small interfering RNA)-mediated knockdown of CDX2 caused a significant reduction in endogenous CFTR transcription in intestinal cells, suggesting that this factor is critical for the maintenance of high levels of CFTR expression in these cells. The ChIP data also demonstrate that these TFs interact with multiple cis-regulatory elements across the CFTR locus, implicating a more global role in intestinal expression of the gene.

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Mangia, Anita, Concetta Saponaro, Alessandro Vagheggini, Giuseppina Opinto, Matteo Centonze, Chiara Vicenti, Ondina Popescu, Maria Pastena, Francesco Giotta, and Nicola Silvestris. "Should Tumor Infiltrating Lymphocytes, Androgen Receptor, and FOXA1 Expression Predict the Clinical Outcome in Triple Negative Breast Cancer Patients?" Cancers 11, no. 9 (September 18, 2019): 1393. http://dx.doi.org/10.3390/cancers11091393.

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Tumor-infiltrating lymphocytes (TILs) are a valuable indicator of the immune microenvironment that plays the central role in new anticancer drugs. TILs have a strong prognostic role in triple negative breast cancer (TNBC). Little is known about the interaction with the androgen receptor (AR) and forkhead box A1 (FOXA1). We analyzed the relationships between TIL levels, AR, and FOXA1 expression and their clinical significance in TNBC patients. Further, we investigated their interaction with other biomarkers like programmed cell death ligand-1 (PD-L1), breast cancer type 1 susceptibility protein (BRCA1), poly (ADP-Ribose) polymerase 1 (PARP1), and Na+/H+ exchanger regulatory factor 1 (NHERF1). The expression of the proteins was evaluated by immunohistochemistry in 124 TNBC samples. TILs were performed adhering to International TILs Working Group 2014 criteria. Cox proportional hazards models were also used to identify risk factors associated with poor prognosis. Multivariate analysis identified TILs as independent prognostic factor of disease free survival (DFS; p = 0.045). A Kaplan–Meyer analysis revealed that the patients with high TILs had a better DFS compared to patients with low TILs (p = 0.037), and the phenotypes TILs−/AR+ and TILs−/FOXA1− had a worse DFS (p = 0.032, p = 0.001 respectively). AR was associated with FOXA1 expression (p = 0.007), and the tumors FOXA1+ presented low levels of TILs (p = 0.028). A poor DFS was observed for AR+/FOXA1+ tumors compared to other TNBCs (p = 0.0117). Low TILs score was associated with poor patients’ survival, and TILs level in combination with AR or FOXA1 expression affected patient’s clinical outcome. In addition, AR+/FOXA1+ phenotype identified a specific subgroup of TNBC patients with poor prognosis. These data may suggest new ways of therapeutic intervention to support current treatments.

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Tsintzas, Kostas, Luke Norton, Kamal Chokkalingam, Nusrat Nizamani, Scott Cooper, Francis Stephens, Rudolf Billeter, and Andrew Bennett. "Independent and combined effects of acute physiological hyperglycaemia and hyperinsulinaemia on metabolic gene expression in human skeletal muscle." Clinical Science 124, no. 11 (February 15, 2013): 675–86. http://dx.doi.org/10.1042/cs20120481.

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Physiological hyperglycaemia and hyperinsulinaemia are strong modulators of gene expression, which underpins some of their well-known effects on insulin action and energy metabolism. The aim of the present study was to examine whether acute in vivo exposure of healthy humans to hyperinsulinaemia and hyperglycaemia have independent or additive effects on expression of key metabolic genes in skeletal muscle. On three randomized occasions, seven young subjects underwent a 4 h (i) hyperinsulinaemic (50 m-units·m−2·min−1) hyperglycaemic (10 mmol/l) clamp (HIHG), (ii) hyperglycaemic (10 mmol/l) euinsulinaemic (5 m-units·m−2·min−1) clamp (LIHG) and (iii) hyperinsulinaemic (50 m-units·m−2·min−1) euglycaemic (4.5 mmol/l) clamp (HING). Muscle biopsies were obtained before and after each clamp for the determination of expression of genes involved in energy metabolism, and phosphorylation of key insulin signalling proteins. Hyperinsulinaemia and hyperglycaemia exerted independent effects with similar direction of modulation on PI3KR1 (phosphatidylinositol 3-kinase, regulatory 1), LXRα (liver X receptor α), PDK4 (pyruvate dehydrogenase kinase 4) and FOXO1 (forkhead box O1A) and produced an additive effect on PI3KR1, the gene that encodes the p85α subunit of PI3K in human skeletal muscle. Acute hyperglycaemia itself altered the expression of genes involved in fatty acid transport and oxidation [fatty acid transporter (CD36), LCAD (long-chain acyl-CoA dehydrogenase) and FOXO1], and lipogenesis [LXRα, ChREBP (carbohydrate-responseelement-binding protein), ABCA1 (ATP-binding cassette transporter A1) and G6PD (glucose-6-phosphate dehydrogenase). Surperimposing hyperinsulinaemia on hyperglycaemia modulated a number of genes involved in insulin signalling, glucose metabolism and intracellular lipid accumulation and exerted an additive effect on PI3KR1. These may be early molecular events that precede the development of glucolipotoxicity and insulin resistance normally associated with more prolonged periods of hyperglycaemia and hyperinsulinaemia.

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Grabowska, Magdalena M., Stephen M. Kelly, Amy L. Reese, Justin M. Cates, Tom C. Case, Jianghong Zhang, David J. DeGraff, et al. "Nfib Regulates Transcriptional Networks That Control the Development of Prostatic Hyperplasia." Endocrinology 157, no. 3 (December 17, 2015): 1094–109. http://dx.doi.org/10.1210/en.2015-1312.

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AbstractA functional complex consisting of androgen receptor (AR) and forkhead box A1 (FOXA1) proteins supports prostatic development, differentiation, and disease. In addition, the interaction of FOXA1 with cofactors such as nuclear factor I (NFI) family members modulates AR target gene expression. However, the global role of specific NFI family members has yet to be described in the prostate. In these studies, chromatin immunoprecipitation followed by DNA sequencing in androgen-dependent LNCaP prostate cancer cells demonstrated that 64.3% of NFIB binding sites are associated with AR and FOXA1 binding sites. Interrogation of published data revealed that genes associated with NFIB binding sites are predominantly induced after dihydrotestosterone treatment of LNCaP cells, whereas NFIB knockdown studies demonstrated that loss of NFIB drives increased AR expression and superinduction of a subset of AR target genes. Notably, genes bound by NFIB only are associated with cell division and cell cycle. To define the role of NFIB in vivo, mouse Nfib knockout prostatic tissue was rescued via renal capsule engraftment. Loss of Nfib expression resulted in prostatic hyperplasia, which did not resolve in response to castration, and an expansion of an intermediate cell population in a small subset of grafts. In human benign prostatic hyperplasia, luminal NFIB loss correlated with more severe disease. Finally, some areas of intermediate cell expansion were also associated with NFIB loss. Taken together, these results show a fundamental role for NFIB as a coregulator of AR action in the prostate and in controlling prostatic hyperplasia.

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Liu, Yang, Yu Fang, Lili Bao, Feng Wu, Shilong Wang, and Siyu Hao. "Intercellular Communication Reveals Therapeutic Potential of Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer." Biomolecules 12, no. 10 (October 14, 2022): 1478. http://dx.doi.org/10.3390/biom12101478.

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(1) Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high intra-tumoral heterogeneity. The epithelial-mesenchymal transition (EMT) is one of the inducers of cancer metastasis and migration. However, the description of the EMT process in TNBC using single-cell RNA sequencing (scRNA-seq) remains unclear. (2) Methods: In this study, we analyzed 8938 cellular gene expression profiles from five TNBC patients. We first scored each malignant cell based on functional pathways to determine its EMT characteristics. Then, a pseudo-time trajectory analysis was employed to characterize the cell trajectories. Furthermore, CellChat was used to identify the cellular communications. (3) Results: We identified 888 epithelium-like and 846 mesenchyme-like malignant cells, respectively. A further pseudo-time trajectory analysis indicated the transition trends from epithelium-like to mesenchyme-like in malignant cells. To characterize the potential regulators of the EMT process, we identified 10 dysregulated transcription factors (TFs) between epithelium-like and mesenchyme-like malignant cells, in which overexpressed forkhead box protein A1 (FOXA1) was recognized as a poor prognosis marker of TNBC. Furthermore, we dissected the cell-cell communications via ligand-receptor (L-R) interactions. We observed that tumor-associated macrophages (TAMs) may support the invasion of malignant epithelial cells, based on CXCL-CXCR2 signaling. The tumor necrosis factor (TNF) signaling pathway secreted by TAMs was identified as an outgoing communication pattern, mediating the communications between monocytes/TAMs and malignant epithelial cells. Alternatively, the TNF-related ligand-receptor (L-R) pairs showed promising clinical implications. Some immunotherapy and anti-neoplastic drugs could interact with the L-R pairs as a potential strategy for the treatment of TNBC. In summary, this study enhances the understanding of the EMT process in the TNBC microenvironment, and dissections of EMT-related cell communications also provided us with potential treatment targets.

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He, Chuan, Shan Lu, Xuan-zhong Wang, Chong-cheng Wang, Lei Wang, Shi-peng Liang, Tian-fei Luo, et al. "FOXO3a protects glioma cells against temozolomide-induced DNA double strand breaks via promotion of BNIP3-mediated mitophagy." Acta Pharmacologica Sinica 42, no. 8 (April 20, 2021): 1324–37. http://dx.doi.org/10.1038/s41401-021-00663-y.

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AbstractFOXO3a (forkhead box transcription factor 3a) is involved in regulating multiple biological processes in cancer cells. BNIP3 (Bcl-2/adenovirus E1B 19-kDa-interacting protein 3) is a receptor accounting for priming damaged mitochondria for autophagic removal. In this study we investigated the role of FOXO3a in regulating the sensitivity of glioma cells to temozolomide (TMZ) and its relationship with BNIP3-mediated mitophagy. We showed that TMZ dosage-dependently inhibited the viability of human U87, U251, T98G, LN18 and rat C6 glioma cells with IC50 values of 135.75, 128.26, 142.65, 155.73 and 111.60 μM, respectively. In U87 and U251 cells, TMZ (200 μM) induced DNA double strand breaks (DSBs) and nuclear translocation of apoptosis inducing factor (AIF), which was accompanied by BNIP3-mediated mitophagy and FOXO3a accumulation in nucleus. TMZ treatment induced intracellular ROS accumulation in U87 and U251 cells via enhancing mitochondrial superoxide, which not only contributed to DNA DSBs and exacerbated mitochondrial dysfunction, but also upregulated FOXO3a expression. Knockdown of FOXO3a aggravated TMZ-induced DNA DSBs and mitochondrial damage, as well as glioma cell death. TMZ treatment not only upregulated BNIP3 and activated autophagy, but also triggered mitophagy by prompting BNIP3 translocation to mitochondria and reinforcing BNIP3 interaction with LC3BII. Inhibition of mitophagy by knocking down BNIP3 with SiRNA or blocking autophagy with 3MA or bafilomycin A1 exacerbated mitochondrial superoxide and intracellular ROS accumulation. Moreover, FOXO3a knockdown inhibited TMZ-induced BNIP3 upregulation and autophagy activation. In addition, we showed that treatment with TMZ (100 mg·kg−1·d−1, ip) for 12 days in C6 cell xenograft mice markedly inhibited tumor growth accompanied by inducing FOXO3a upregulation, oxidative stress and BNIP3-mediated mitophagy in tumor tissues. These results demonstrate that FOXO3a attenuates temozolomide-induced DNA double strand breaks in human glioma cells via promoting BNIP3-mediated mitophagy.

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Kubouchi, Koichi, Kyosuke Shimada, Takamichi Yokoe, and Yutaka Tsutsumi. "Avoidance and Period-Shortening of Neoadjuvant Chemotherapy Against Triple-Negative Breast Cancer in Stages I and II: Importance of Ki-67 Labeling Index and the Recognition of Apocrine-Type Lesions." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382094324. http://dx.doi.org/10.1177/1533033820943246.

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Background: Triple-negative breast cancer encompasses heterogeneous subtypes. Neoadjuvant chemotherapy is ineffective against some triple-negative breast cancers, while others show a favorable prognosis despite chemoresistance. Methods: A total of 51 cases with stages I and II triple-negative breast cancer were analyzed; 34 triple-negative breast cancers treated with neoadjuvant chemotherapy were divided into “good responders” (n = 22), showing therapeutic effect G2b or G3 in surgical specimens, and “poor responders” with therapeutic effect G0, G1a, G1b, and G2a (n = 12). Neoadjuvant chemotherapy was spared in 17 cases (non-neoadjuvant chemotherapy group). Apocrine-type triple-negative breast cancer was defined as triple-negative breast cancer immunoreactive for both androgen receptor and forkhead-box protein A1. Triple-negative breast cancer other than apocrine-type (n = 16) and special types (myoepithelial, medullary, adenoid cystic, and spindle cell carcinomas, n = 6) was categorized as basal-like subtype (n = 29). Prognosis was evaluated in each category. Results: Neoadjuvant chemotherapy provoked significant effects against basal-like triple-negative breast cancer with high Ki-67 labeling (≧50%), and tumor-infiltrating lymphocytes predicted high chemosensitivity. Neoadjuvant chemotherapy was avoidable in triple-negative breast cancer of apocrine- and special types showing low (<50%) Ki-67 labeling. Ten (59%) lesions in the non-neoadjuvant chemotherapy group belonged to the apocrine-type. When clinical complete remission shown by contrast-enhanced magnetic resonance imaging was reached in the course of neoadjuvant chemotherapy against basal-like triple-negative breast cancer, the neoadjuvant chemotherapy period was shortened in 14 (64%) of 22 good responders. Disease-free and overall survival rates were excellent in all groups. Conclusions: The following 2 hypothetical proposals should be proven by large-scale clinical trials. Immunohistochemical recognition of apocrine-type triple-negative breast cancer with low Ki-67 labeling is important for avoiding ineffective/unnecessary neoadjuvant chemotherapy. By employing appropriate clinical imaging, period-shortening is achievable in basal-like triple-negative breast cancer with high Ki-67 labeling.

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Brea, Lourdes T., Xiaohai Wang, and Jindan Yu. "Epithelial Transcription Factor FOXA1 Regulates Prostate Cancer Immune Response." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A1017. http://dx.doi.org/10.1210/jendso/bvab048.2080.

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Abstract Background : While localized prostate cancer (PCa) can be mitigated by surgery and radiation, metastatic PCa remains a challenge to treat. Androgen deprivation therapies and androgen receptor (AR) pathway inhibitors are mainstay treatments for advanced PCa. Yet, resistance often develops leading to castration-resistant prostate cancer (CRPC). Forkhead Box A1 (FOXA1) is a pioneer transcription factor that plays pivotal roles in regulating AR activity and promoting epithelial differentiation. Studies have shown that FOXA1 is frequently downregulated in CRPC tumors. Congruently, FOXA1 loss is reported to induce aberrant AR signaling, epithelial-mesenchymal transition, and PCa de-differentiation. However, the role of FOXA1 in regulating PCa immune response, an area of much interest recently, has not been reported. CRPC has shown poor response to immune checkpoint inhibitors, due to its immunosuppressive nature. A better understanding of the tumor intrinsic mechanisms regulating PCa tumor immunity will inform the design of better targeted immunotherapeutic approaches. Methods: We performed RNA-seq, ChIP-seq, qPCR, western blot, and ELISA analyses to evaluate how FOXA1 regulates inflammatory response genes. We utilized an in vitro macrophage infiltration transwell assay, in which M2-like macrophages were added to the upper chamber and PCa cells were plated in the lower chamber, to examine how perturbations to PCa cells affect macrophage migration. Finally, we performed bioinformatic analyses of patient datasets to confirm the clinical relevance of FOXA1 repression of inflammatory genes in PCa. Results: Through integration of RNA-seq and ChIP-seq data, we uncovered a novel function of FOXA1 in suppressing inflammatory response pathways. In accordance, patient data analyses revealed that inflammatory response genes were upregulated in FOXA1-low PCa tumors. Mechanistically, we showed that FOXA1 proteins bound an intragenic enhancer of Hypoxia-inducible factor 1-alpha (HIF1A) gene to directly repress its expression, such that FOXA1 loss induced HIF1A upregulation. We further showed that Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) became upregulated upon FOXA1 depletion in a HIF1A-dependent manner. This led to infiltration by immunosuppressive, tumor promoting M2-like macrophages. Inhibiting this HIF1A-CCL2 axis with a HIF1A inhibitor or CCL2 neutralizing antibody blocked macrophage infiltration. Future studies using immunocompetent mouse models are needed to confirm the effect of FOXA1 on macrophage infiltration in vivo and evaluate the preclinical potential of targeting the FOXA1-HIF1A-CCL2 axis in CRPC. Conclusion: This study proposes a novel role for FOXA1 loss in promoting macrophage infiltration via the HIF1A-CCL2 axis. Moreover, our findings suggest that targeting this axis may be a promising approach for the treatment of FOXA1-low CRPC tumors.

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Luo, Xin, Zhulin Yang, Xiao Liu, Ziru Liu, Xiongying Miao, Daiqiang Li, Qiong Zou, and Yuan Yuan. "The clinicopathological significance of forkhead box P1 and forkhead box O3a in pancreatic ductal adenocarcinomas." Tumor Biology 39, no. 5 (May 2017): 101042831769912. http://dx.doi.org/10.1177/1010428317699129.

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Pancreatic ductal adenocarcinoma is a highly malignant tumor with poor prognosis, and the biomarkers for the early diagnosis, targeting therapy, and prognosis are still not clinically available. This study investigated the expression of forkhead box P1 and forkhead box O3a proteins in human pancreatic ductal adenocarcinoma tumor tissues and pancreatic tissues with and without benign lesions using immunohistochemical staining. Results showed that the positive rates of forkhead box P1 and forkhead box O3a protein expression were significantly lower in pancreatic ductal adenocarcinoma tumors compared to peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (p < 0.01). Pancreatic tissues with negative forkhead box P1 and forkhead box O3a protein expression exhibited dysplasia or intraepithelial neoplasia. The positive rates of forkhead box P1 and forkhead box O3a expression were significantly lower in cases with tumor mass >5 cm, lymph node metastasis, invasion to surrounding tissues and organs, and tumor–node–metastasis III + IV stage disease compared to cases with tumor mass ⩽5 cm (p < 0.05), no lymph node metastasis (p < 0.001 and p = 0.001, respectively), no invasion (p = 0.003 and p = 0.004, respectively), and tumor–node–metastasis I or II stage disease (p < 0.05). Kaplan–Meier survival analysis showed that pancreatic ductal adenocarcinoma patients with negative forkhead box P1 and forkhead box O3a expression survived significantly shorter than patients with positive forkhead box P1 and forkhead box O3a expression (p = 0.000). Cox multivariate analysis revealed that negative forkhead box P1 and forkhead box O3a expression was an independent poor prognosis factor in pancreatic ductal adenocarcinoma patients. The area under the curve of a receiver operating characteristic curve was 0.642 for forkhead box P1 (95% confidence interval: 0.553–0.730) and 0.655 for forkhead box O3a (95% confidence interval: 0.6568–0.742). Loss of forkhead box P1 and forkhead box O3a protein expression is associated with carcinogenesis, progression, and poor prognosis in patients with pancreatic ductal adenocarcinomas.

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Song, Lan, Bin Zhang, Yansheng Feng, Xinjing Luo, Xing Wei, and Xianzhong Xiao. "A Role for Forkhead Box A1 in Acute Lung Injury." Inflammation 32, no. 5 (August 1, 2009): 322–32. http://dx.doi.org/10.1007/s10753-009-9139-x.

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Tan, Congcong, Hui Lyu, sanbao Ruan, and bolin Liu. "Abstract 2969: Histone deacetylase (HDAC) inhibitors exhibit antitumor activity in triple negative breast cancer via suppression of HER3 triggered signaling." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2969. http://dx.doi.org/10.1158/1538-7445.am2022-2969.

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Abstract Introduction: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high rate of recurrence and refractoriness due to lack of well-defined molecular targets. Human epidermal growth factor receptor 3 (HER3) is differentially expressed in TNBC cells. Numerous studies indicate that elevated expression of HER3, through its dimerization with another receptor, is a major cause of treatment failure in human cancers. To date, there is no FDA-approved HER3-targeted cancer therapy. HDAC inhibitors (HDACis) have been approved for the treatment of refractory or relapsed cutaneous T cell lymphomas and show potency in TNBC cells. However, it remains unclear whether the HDACis may alter HER3 expression to influence the downstream signaling in HER3-overexpressing (HER3high) TNBC. Methods: Colony formation, MTS and LIVE/DEAD cell staining assays were used to detect cell viability. Apoptosis was detected by flow cytometry assays. QRT-PCR, western blots and immunohistochemistry were performed to determine the expression and activation of genes and/or proteins. Co-immunoprecipitation was performed to assess the interaction between proteins. Lentivirus vectors containing cDNA or shRNAs were used to overexpress or knockdown gene expression. Chromatin immunoprecipitation-quantitative PCR and dual luciferase reporter assays were performed to elucidate the regulatory role of gene transcription. Results: Elevated expression of HER3 were observed in approximately half of the TNBC specimens and cell lines tested. HER3 was co-expressed and formed heterodimers with epidermal growth factor receptor (EGFR) to activate the PI-3K/Akt signaling in HER3high-TNBC cells. Panobinostat and romidepsin induced growth inhibition and apoptosis in HER3high-TNBC cells via downregulating HER3 expression and inhibiting PI-3K/Akt signaling. Significantly, HDACis in combination with an EGFR inhibitor (gefitinib) or an Akt inhibitor (Akti1/2) synergistically enhanced the anti-survival effects on HER3high-TNBC cells. Besides, analyses of gene expression profiling datasets revealed a significantly positive correlation between expression of HER3 and transcription factor forkhead box A1 (FOXA1). Further studies discovered that FOXA1 activated HER3 expression through directly binding to HER3 promoter. Moreover, ectopic expression of FOXA1 not only rescued the expression of HER3-downregulated by HDACis, but also attenuated these HDACis-mediated anti-survival effects on HER3high-TNBC cells. Conclusion: HDAC inhibitors exhibits potent inhibitory effects on HER3high-TNBC cells via downregulation of FOXA1-mediated repression of HER3 gene transcription. Our data suggest that epigenetic targeting of FOXA1-HER3/EGFR-PI-3K/Akt signaling axis may be an effective therapeutic strategy for eradication of HER3high-TNBC tumors. Citation Format: Congcong Tan, Hui Lyu, sanbao Ruan, bolin Liu. Histone deacetylase (HDAC) inhibitors exhibit antitumor activity in triple negative breast cancer via suppression of HER3 triggered signaling [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 2969.

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Gao, N. "Forkhead box A1 regulates prostate ductal morphogenesis and promotes epithelial cell maturation." Development 132, no. 15 (June 23, 2005): 3431–43. http://dx.doi.org/10.1242/dev.01917.

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Habashy, Hany Onsy, Desmond G. Powe, Emad A. Rakha, Graham Ball, Claire Paish, Julia Gee, Robert I. Nicholson, and Ian O. Ellis. "Forkhead-box A1 (FOXA1) expression in breast cancer and its prognostic significance." European Journal of Cancer 44, no. 11 (July 2008): 1541–51. http://dx.doi.org/10.1016/j.ejca.2008.04.020.

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Wang, Jingyun, Yiding Bian, Yun Liao, Ye Xia, and Xiaoping Wan. "Forkhead-box A1 induces cell senescence in endometrial cancer by regulating p16INK4a." Oncology Reports 36, no. 2 (June 23, 2016): 795–802. http://dx.doi.org/10.3892/or.2016.4907.

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Nik Tavakoli, Nasim, Brett D. Hambly, David R. Sullivan, and Shisan Bao. "Forkhead box protein 3: Essential immune regulatory role." International Journal of Biochemistry & Cell Biology 40, no. 11 (2008): 2369–73. http://dx.doi.org/10.1016/j.biocel.2007.10.004.

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Deqiang, Hou, Gao Yufeng, Bai Ning, and Dong Yu. "Isoliquiritigenin Inhibits Proliferation and Induces Apoptosis in Tongue Squamous Cell Carcinoma by Modulating miR-21/FOXG1 Pathway." Current Topics in Nutraceutical Research 17, no. 4 (July 30, 2019): 463–69. http://dx.doi.org/10.37290/ctnr2641-452x.17:463-469.

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Isoliquiritigenin is a flavonoid commonly found in liquorice and has been identified as a potent anti-tumor agent. The aim of this study was to investigate whether isoliquiritigenin regulates the proliferation and apoptosis of tongue squamous cell carcinoma cells by regulating forkhead box G1 expression via miR-21. MTT assay and flow cytometry were used to analyze cell proliferation and apoptosis, respectively. Quantitative real time polymerase chain reaction and western blotting were used to detect mRNA and protein expression levels, respectively. The relationship between miR-21 and forkhead box G1 was detected by dual luciferase assay. Isoliquiritigenin inhibited proliferation and induced apoptosis of tongue squamous cell carcinoma cells, and decreased miR-21 levels and promoted forkhead box G1 expression. Forkhead box G1 was then identified as a target of miR-21 and ISL could promote forkhead box G1 expression by inhibiting miR-21. Further analysis suggested that upregulation of miR-21 improved proliferation and suppressed apoptosis of tongue squamous cell carcinoma cells by inhibiting forkhead box G1 expression. Finally, our results revealed that isoliquiritigenin inhibited proliferation and induced apoptosis of tongue squamous cell carcinoma cells by regulating miR-21. Isoliquiritigenin might act as a novel therapeutic treatment for tongue squamous cell carcinoma cells through up-regulation of forkhead box G1 expression via inhibiting miR-21expression.

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Adamczyk-Gruszka, Olga, Agata Horecka-Lewitowicz, Jakub Gruszka, Monika Wawszczak-Kasza, Agnieszka Strzelecka, and Piotr Lewitowicz. "Endometrial Cancer in Aspect of Forkhead Box Protein Contribution." International Journal of Environmental Research and Public Health 19, no. 16 (August 21, 2022): 10403. http://dx.doi.org/10.3390/ijerph191610403.

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(1) Background: The present study aimed to investigate the influence of forkhead box (FOX) on endometrial cancer (EC) progression. For a better understanding, the driving mechanisms are vital to identifying correlations between genes and their regulators. (2) Methods: The study enrolled one hundred and three white female patients with confirmed EC. For the analysis, we used next-generation sequencing with the Hot Spot Cancer Panel provided by Illumina Inc., San Diego, CA, USA, and an immunohistochemical analysis of FOXA1, FOXP1, and estrogen receptors. (3) Results: FOXA1 silencing led to a worse outcome based on the correlation with FOXA1 (test log-rank p = 0.04220 and HR 2.66, p = 0.033). Moreover, FOX proteins were closely correlated with TP53 and KRAS mutation. (4) Conclusions: Our study confirmed previous reports about FOX box protein in the regulation of tumor growth. A remarkable observation about the unclear crosstalk with crucial genes, as TP53 and KRAS need deeper investigation.

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Wang, Chiung-Min, William Harry Yang, Leticia Cardoso, Ninoska Gutierrez, Richard Henry Yang, and Wei-Hsiung Yang. "Forkhead Box Protein P3 (FOXP3) Represses ATF3 Transcriptional Activity." International Journal of Molecular Sciences 22, no. 21 (October 22, 2021): 11400. http://dx.doi.org/10.3390/ijms222111400.

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Activating transcription factor 3 (ATF3), a transcription factor and acute stress sensor, is rapidly induced by a variety of pathophysiological signals and is essential in the complex processes in cellular stress response. FOXP3, a well-known breast and prostate tumor suppressor from the X chromosome, is a novel transcriptional repressor for several oncogenes. However, it remains unknown whether ATF3 is the target protein of FOXP3. Herein, we demonstrate that ATF3 expression is regulated by FOXP3. Firstly, we observed that overexpression of FOXP3 reduced ATF3 protein level. Moreover, knockdown FOXP3 by siRNA increased ATF3 expression. Secondly, FOXP3 dose-dependently reduced ATF3 promoter activity in the luciferase reporter assay. Since FOXP3 is regulated by post-translational modifications (PTMs), we next investigated whether PTMs affect FOXP3-mediated ATF3 expression. Interestingly, we observed that phosphorylation mutation on FOXP3 (Y342F) significantly abolished FOXP3-mediated ATF3 expression. However, other PTM mutations on FOXP3, including S418 phosphorylation, K263 acetylation and ubiquitination, and K268 acetylation and ubiquitination, did not alter FOXP3-mediated ATF3 expression. Finally, the FOXP3 binding site was found on ATF3 promoter region by deletion and mutagenesis analysis. Taken together, our results suggest that FOXP3 functions as a novel regulator of ATF3 and that this novel event may be involved in tumor development and progression.

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Afaf T, Elnashar, and Youssef Esraa M. "And p53 in epithelial immunohisto- chemical expression of Forkhead Box (FOX) A1 ovarian cancer." Clinical Journal of Obstetrics and Gynecology 5, no. 2 (May 20, 2022): 061–66. http://dx.doi.org/10.29328/journal.cjog.1001109.

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Background: Ovarian cancer (OC) is the fifth cause of cancer mortality in females. There were an estimated 300,000 new cases of OC diagnosed worldwide in 2018, corresponding to 3.4% of all cancer cases among women. The high mortality rate of OC attributed to asymptomatic growth of the tumor leads to its diagnosis at advanced stages. About 85% - 90% of OC are epithelial including serous, endometrioid, clear cell, and mucinous carcinoma. Aim: To study the immunohistochemical (IHC) expression of FOXA1 and p53 in epithelial OC and its association with prognostic indicators such as age, tumor size, stage, grade, and histological type. Materials and methods: The study included 52 cases with EOC from the pathology department, faculty of medicine, Aswan, and Sohag Universities, in the period from January 2017 to December 2019. This study involved 52 patients with OC and a median age of 53 years. Different histological types were included as 37 serous, 12 mucinous, 1 case endometroid 2 cases clear cell OC. The study cases were classified into 22 Grade I, 16 Grade II, and 20 Grade III. About 22 cases were at stage I, 9 at stage II, 11 at stage III, and 10 at stage IV. Tissue sections were stained using the IHC technique with FOX A1 at a dilution of 1:100 and p53 at 1:100. Results: A statistically significant correlation was found between FOX A1 expression and advanced patient's age, high grade, advanced stage, ruptured capsule, and ascites, regardless of tumor laterality. No significant association was found between p53 immunoexpression and the same clinic-pathological parameters although p53 was associated with serious type. Conclusion: FOXA1 immunoexpression in EOC is considered a poor prognostic factor in EOC. FOXA1 could be a potential therapeutic target and prognostic marker in EOC.

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