Journal articles on the topic 'Prostate cancer; epigenetic modification'
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1
Albany, Costantine, Ajjai S. Alva, Ana M. Aparicio, Rakesh Singal, Sarvari Yellapragada, Guru Sonpavde, and Noah M. Hahn. "Epigenetics in Prostate Cancer." Prostate Cancer 2011 (2011): 1–12. http://dx.doi.org/10.1155/2011/580318.
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Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a “normal” epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.
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Donkena, Krishna Vanaja, Charles Y. F. Young, and Donald J. Tindall. "Oxidative Stress and DNA Methylation in Prostate Cancer." Obstetrics and Gynecology International 2010 (2010): 1–14. http://dx.doi.org/10.1155/2010/302051.
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The protective effects of fruits, vegetables, and other foods on prostate cancer may be due to their antioxidant properties. An imbalance in the oxidative stress/antioxidant status is observed in prostate cancer patients. Genome oxidative damage in prostate cancer patients is associated with higher lipid peroxidation and lower antioxidant levels. Oxygen radicals are associated with different steps of carcinogenesis, including structural DNA damage, epigenetic changes, and protein and lipid alterations. Epigenetics affects genetic regulation, cellular differentiation, embryology, aging, cancer, and other diseases. DNA methylation is perhaps the most extensively studied epigenetic modification, which plays an important role in the regulation of gene expression and chromatin architecture, in association with histone modification and other chromatin-associated proteins. This review will provide a broad overview of the interplay of oxidative stress and DNA methylation, DNA methylation changes in regulation of gene expression, lifestyle changes for prostate cancer prevention, DNA methylation as biomarkers for prostate cancer, methods for detection of methylation, and clinical application of DNA methylation inhibitors for epigenetic therapy.
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Zheng, Jianghua, Jinglong Wang, Xueqing Sun, Mingang Hao, Tao Ding, Dan Xiong, Xiumin Wang, et al. "HIC1 Modulates Prostate Cancer Progression by Epigenetic Modification." Clinical Cancer Research 19, no. 6 (January 22, 2013): 1400–1410. http://dx.doi.org/10.1158/1078-0432.ccr-12-2888.
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Ngollo, Marjolaine, Aslihan Dagdemir, Seher Karsli-Ceppioglu, Gaelle Judes, Amaury Pajon, Frederique Penault-Llorca, Jean-Paul Boiteux, Yves-Jean Bignon, Laurent Guy, and Dominique J. Bernard-Gallon. "Epigenetic modifications in prostate cancer." Epigenomics 6, no. 4 (August 2014): 415–26. http://dx.doi.org/10.2217/epi.14.34.
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Ippolito, Luigi, Giuseppina Comito, Matteo Parri, Marta Iozzo, Assia Duatti, Francesca Virgilio, Nicla Lorito, et al. "Lactate Rewires Lipid Metabolism and Sustains a Metabolic–Epigenetic Axis in Prostate Cancer." Cancer Research 82, no. 7 (February 8, 2022): 1267–82. http://dx.doi.org/10.1158/0008-5472.can-21-0914.
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Abstract Lactate is an abundant oncometabolite in the tumor environment. In prostate cancer, cancer-associated fibroblasts (CAF) are major contributors of secreted lactate, which can be taken up by cancer cells to sustain mitochondrial metabolism. However, how lactate impacts transcriptional regulation in tumors has yet to be fully elucidated. Here, we describe a mechanism by which CAF-secreted lactate is able to increase the expression of genes involved in lipid metabolism in prostate cancer cells. This regulation enhanced intracellular lipid accumulation in lipid droplets (LD) and provided acetyl moieties for histone acetylation, establishing a regulatory loop between metabolites and epigenetic modification. Inhibition of this loop by targeting the bromodomain and extraterminal protein family of histone acetylation readers suppressed the expression of perilipin 2 (PLIN2), a crucial component of LDs, disrupting lactate-dependent lipid metabolic rewiring. Inhibition of this CAF-induced metabolic–epigenetic regulatory loop in vivo reduced growth and metastasis of prostate cancer cells, demonstrating its translational relevance as a therapeutic target in prostate cancer. Clinically, PLIN2 expression was elevated in tumors with a higher Gleason grade and in castration-resistant prostate cancer compared with primary prostate cancer. Overall, these findings show that lactate has both a metabolic and an epigenetic role in promoting prostate cancer progression. Significance: This work shows that stromal-derived lactate induces accumulation of lipid droplets, stimulates epigenetic rewiring, and fosters metastatic potential in prostate cancer.
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Kgatle, Mankgopo M., Asgar A. Kalla, Muhammed M. Islam, Mike Sathekge, and Razia Moorad. "Prostate Cancer: Epigenetic Alterations, Risk Factors, and Therapy." Prostate Cancer 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/5653862.
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Prostate cancer (PCa) is the most prevalent urological cancer that affects aging men in South Africa, and mechanisms underlying prostate tumorigenesis remain elusive. Research advancements in the field of PCa and epigenetics have allowed for the identification of specific alterations that occur beyond genetics but are still critically important in the pathogenesis of tumorigenesis. Anomalous epigenetic changes associated with PCa include histone modifications, DNA methylation, and noncoding miRNA. These mechanisms regulate and silence hundreds of target genes including some which are key components of cellular signalling pathways that, when perturbed, promote tumorigenesis. Elucidation of mechanisms underlying epigenetic alterations and the manner in which these mechanisms interact in regulating gene transcription in PCa are an unmet necessity that may lead to novel chemotherapeutic approaches. This will, therefore, aid in developing combination therapies that will target multiple epigenetic pathways, which can be used in conjunction with the current conventional PCa treatment.
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Orea, María J., Javier C. Angulo, Ana González-Corpas, David Echegaray, Marcos Marvá, María V. T. Lobo, Begoña Colás, and Santiago Ropero. "Claudin-3 Loss of Expression Is a Prognostic Marker in Castration-Resistant Prostate Cancer." International Journal of Molecular Sciences 24, no. 1 (January 2, 2023): 803. http://dx.doi.org/10.3390/ijms24010803.
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Castration-resistant prostate cancer (CRPC) development is the foremost concern after treatment of patients with high risk with locally advanced or metastatic prostate cancer. Androgen receptor (AR) is the main driver of CRPC development, through its interaction with epigenetic modifier genes, placing epigenetics modifications in the forefront of CRPC development. Comparing the DNA methylation and expression profile of androgen-sensitive and -refractory prostate cancer cells, we describe the epigenetic silencing of claudin-3 (CLDN3) in AR positive cells resistant to androgen deprivation (LNCaP-abl). CLDN3 silencing was associated with DNA methylation, loss of histone acetylation and H3K27 methylation, and was re-expressed by the combined treatment with the epigenetic modulators Aza and SAHA. From a functional point of view, CLDN3 loss was associated with increased cellular invasion. Immunohistochemical analysis showed decreased CLDN3 expression in samples from CRPC patients. Interestingly, CLDN3 expression was significantly decreased in samples from patients with high total Gleason score (≥8) and locally advanced tumors. Finally, CLDN3 loss of expression was associated with worse disease-free survival and time to clinical progression. In conclusion, our findings strongly indicate that epigenetic silencing of CLDN3 is a common event in CRPC that could be useful as a molecular marker for the prognosis of prostate cancer patients and to discriminate aggressive from indolent prostate tumors.
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López, Judith, Ana M. Añazco-Guenkova, Óscar Monteagudo-García, and Sandra Blanco. "Epigenetic and Epitranscriptomic Control in Prostate Cancer." Genes 13, no. 2 (February 18, 2022): 378. http://dx.doi.org/10.3390/genes13020378.
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The initiation of prostate cancer has been long associated with DNA copy-number alterations, the loss of specific chromosomal regions and gene fusions, and driver mutations, especially those of the Androgen Receptor. Non-mutational events, particularly DNA and RNA epigenetic dysregulation, are emerging as key players in tumorigenesis. In this review we summarize the molecular changes linked to epigenetic and epitranscriptomic dysregulation in prostate cancer and the role that alterations to DNA and RNA modifications play in the initiation and progression of prostate cancer.
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Bartkowiak-Wieczorek, Joanna, Radosław Kujawski, Anna Bogacz, and Marcin Ożarowski. "An introduction to genetic and epigenetic changes in prostate gland – implications in efficacy of phytotherapy of benign prostatic hyperplasia and prostate cancer." Journal of Medical Science 84, no. 2 (June 30, 2015): 97–103. http://dx.doi.org/10.20883/medical.e23.
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The usage of classical pharmacological treatment of prostate diseases causes the risk of a number of side effects therefore the researchers are looking for new pharmacologically active molecules, including those contained in the plant extracts. The most widely studied is the lipido-sterolic extract from Serenoa repens (saw palmetto), water extract from Camellia sinensis (green tea) and several cruciferous vegetables. The molecular mechanisms underlying of the development and the progression of prostate disorders, especially benign prostatic hyperplasia (BPH) and prostate cancer (PC), remain still poorly understood. The development of pathologically changed prostate cells proliferation involves many factors, including genetic alterations, such as mutations, and epigenetic changes, appear to contribute to the transformation and progression of prostate cancer. In this paper we suggest that the knowledge of epigenetic modifications presented in this paper introduces the new point of view concerning the possibility of action of plant substances used in prevention and symptomatic treatment of BPH and prostate cancer. Thus, identification of the epigenetic modifications involved on the one hand in the development and progression of BPH / PC, on the other influencing the efficacy and safety of potential phytotherapeutics will be helpful in identifying its novel therapeutic strategy.
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Cimadamore, Alessia, Silvia Gasparrini, Marina Scarpelli, Andrea Doria, Roberta Mazzucchelli, Francesco Massari, Liang Cheng, Antonio Lopez-Beltran, and Rodolfo Montironi. "Epigenetic Modifications and Modulators in Prostate Cancer." Critical Reviews™ in Oncogenesis 22, no. 5-6 (2017): 439–50. http://dx.doi.org/10.1615/critrevoncog.2017020964.
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Abbas, Ata, William Patterson, and Philippe T. Georgel. "The epigenetic potentials of dietary polyphenols in prostate cancer management." Biochemistry and Cell Biology 91, no. 6 (December 2013): 361–68. http://dx.doi.org/10.1139/bcb-2012-0044.
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Prostate cancer is a disease that is greatly affected by lifestyle, particularly diet, and is more prevalent in US and European countries compared with South and East Asia. Among several known causes and risk factors, nutrition plays an important role in prostate cancer pathogenesis. Various dietary components including polyphenols have been shown to possess anticancer properties. Dietary polyphenols have been the subject of extensive studies for the last decade because of their anticancer and chemopreventive potentials. Besides possessing various antitumor properties, dietary polyphenols also contribute to epigenetic changes associated with the fate of cancer cells and have emerged as potential drugs for therapeutic intervention. Various polyphenols have been shown to affect DNA methylation, histone posttranslational modifications, and microRNA expression patterns in prostate cancer. In this review, we discuss the contribution of dietary polyphenols to various epigenetic modifications in prostate cancer. Since prostate cancer and diet are intimately associated, polyphenol-rich diets that epigenetically modify tumor biology have great significance in the prevention and management of prostate cancer.
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Wu, Peng, Ziyi Cao, and Song Wu. "New Progress of Epigenetic Biomarkers in Urological Cancer." Disease Markers 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/9864047.
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Urological cancers consist of bladder, kidney, prostate, and testis cancers and they are generally silenced at their early stage, which leads to the loss of the best opportunity for early diagnosis and treatment. Desired biomarkers are scarce for urological cancers and current biomarkers are lack of specificity and sensitivity. Epigenetic alterations are characteristic of nearly all kinds of human malignances including DNA methylation, histone modification, and miRNA regulation. Besides, the detection of these epigenetic conditions is easily accessible especially for urine, best target for monitoring the diseases of urinary system. Here, we summarize some new progress about epigenetic biomarkers in urological cancers, hoping to provide new thoughts for the diagnosis, treatment, and prognosis of urological cancers.
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Yu, Chenglong, Ee Ming Wong, Jihoon Eric Joo, Allison M. Hodge, Enes Makalic, Daniel Schmidt, Daniel D. Buchanan, et al. "Epigenetic Drift Association with Cancer Risk and Survival, and Modification by Sex." Cancers 13, no. 8 (April 14, 2021): 1881. http://dx.doi.org/10.3390/cancers13081881.
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To investigate age- and sex-specific DNA methylation alterations related to cancer risk and survival, we used matched case–control studies of colorectal (n = 835), gastric (n = 170), kidney (n = 143), lung (n = 332), prostate (n = 869) and urothelial (n = 428) cancers, and mature B-cell lymphoma (n = 438). Linear mixed-effects models were conducted to identify age-, sex- and age-by-sex-associated methylation markers using a discovery (controls)-replication (cases) strategy. Replication was further examined using summary statistics from Generation Scotland (GS). Associations between replicated markers and risk of and survival from cancer were assessed using conditional logistic regression and Cox models (hazard ratios (HR)), respectively. We found 32,659, 23,141 and 48 CpGs with replicated associations for age, sex and age-by-sex, respectively. The replication rates for these CpGs using GS summary data were 94%, 86% and 91%, respectively. Significant associations for cancer risk and survival were identified at some individual age-related CpGs. Opposite to previous findings using epigenetic clocks, there was a strong negative trend in the association between epigenetic drift and risk of colorectal cancer. Methylation at two CpGs overlapping TMEM49 and ARX genes was associated with survival of overall (HR = 0.91, p = 7.7 × 10−4) and colorectal (HR = 1.52, p = 1.8 × 10−4) cancer, respectively, with significant age-by-sex interaction. Our results may provide markers for cancer early detection and prognosis prediction.
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Sulek, Jay E., Samuel P. Robinson, Albert A. Petrossian, Shaoqing Zhou, Ekaterine Goliadze, Masoud H. Manjili, Amir Toor, and Georgi Guruli. "Role of Epigenetic Modification and Immunomodulation in a Murine Prostate Cancer Model." Prostate 77, no. 4 (November 8, 2016): 361–73. http://dx.doi.org/10.1002/pros.23275.
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Lopes, Nair, Mariana Brütt Pacheco, Diana Soares-Fernandes, Margareta P. Correia, Vânia Camilo, Rui Henrique, and Carmen Jerónimo. "Hydralazine and Enzalutamide: Synergistic Partners against Prostate Cancer." Biomedicines 9, no. 8 (August 7, 2021): 976. http://dx.doi.org/10.3390/biomedicines9080976.
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Advanced prostate cancers frequently develop resistance to androgen-deprivation therapy with serious implications for patient survival. Considering their importance in this type of neoplasia, epigenetic modifications have drawn attention as alternative treatment strategies. The aim of this study was to assess the antitumoral effects of the combination of hydralazine, a DNA methylation inhibitor, with enzalutamide, an antagonist of the androgen receptor, in prostate cancer cell lines. Several biological parameters, such as cell viability, proliferation, DNA damage, and apoptosis, as well as clonogenic and invasive potential, were evaluated. The individual treatments with hydralazine and enzalutamide exerted growth-inhibitory effects in prostate cancer cells and their combined treatment displayed synergistic effects. The combination of these two drugs was very effective in decreasing malignant features of prostate cancer and may become an alternative therapeutic option for prostate cancer patient management.
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Perry, Antoinette S., Ruth Foley, Karen Woodson, and Mark Lawler. "The emerging roles of DNA methylation in the clinical management of prostate cancer." Endocrine-Related Cancer 13, no. 2 (June 2006): 357–77. http://dx.doi.org/10.1677/erc.1.01184.
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Aberrant DNA methylation is one of the hallmarks of carcinogenesis and has been recognized in cancer cells for more than 20 years. The role of DNA methylation in malignant transformation of the prostate has been intensely studied, from its contribution to the early stages of tumour development to the advanced stages of androgen independence. The most significant advances have involved the discovery of numerous targets such as GSTP1, Ras-association domain family 1A (RASSF1A) and retinoic acid receptor β2 (RARβ2) that become inactivated through promoter hypermethylation during the course of disease initiation and progression. This has provided the basis for translational research into methylation biomarkers for early detection and prognosis of prostate cancer. Investigations into the causes of these methylation events have yielded little definitive data. Aberrant hypomethylation and how it impacts upon prostate cancer has been less well studied. Herein we discuss the major developments in the fields of prostate cancer and DNA methylation, and how this epigenetic modification can be harnessed to address some of the key issues impeding the successful clinical management of prostate cancer.
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Yasmin, Rehana, Sami Siraj, Amjad Hassan, Abdul Rehman Khan, Rashda Abbasi, and Nafees Ahmad. "Epigenetic Regulation of Inflammatory Cytokines and Associated Genes in Human Malignancies." Mediators of Inflammation 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/201703.
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Inflammation is a multifaceted defense response of immune system against infection. Chronic inflammation has been implicated as an imminent threat for major human malignancies and is directly linked to various steps involved in tumorigenesis. Inflammatory cytokines, interleukins, interferons, transforming growth factors, chemokines, and adhesion molecules have been associated with chronic inflammation. Numerous cytokines are reported to be aberrantly regulated by different epigenetic mechanisms like DNA methylation and histone modifications in tumor tissues, contributing to pathogenesis of tumor in multiple ways. Some of these cytokines also work as epigenetic regulators of other crucial genes in tumor biology, either directly or indirectly. Such regulations are reported in lung, breast, cervical, gastric, colorectal, pancreatic, prostate, and head and neck cancers. Epigenetics of inflammatory mediators in cancer is currently subject of extensive research. These investigations may help in understanding cancer biology and to develop effective therapeutic strategies. The purpose of this paper is to have a brief view of the aberrant regulation of inflammatory cytokines in human malignancies.
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Abbas, Ata, J. Adam Hall, William L. Patterson, Emily Ho, Anna Hsu, Fahd Al-Mulla, and Philippe T. Georgel. "Sulforaphane modulates telomerase activity via epigenetic regulation in prostate cancer cell lines." Biochemistry and Cell Biology 94, no. 1 (February 2016): 71–81. http://dx.doi.org/10.1139/bcb-2015-0038.
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Epidemiologic studies have revealed that diets rich in sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables, are associated with a marked decrease in prostate cancer incidence. The chemo-preventive role of SFN is associated with its histone de-acetylase inhibitor activity. However, the effect of SFN on chromatin composition and dynamic folding, especially in relation to HDAC inhibitor activity, remains poorly understood. In this study, we found that SFN can inhibit the expression and activity of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, in 2 prostate cancer cell lines. This decrease in gene expression is correlated with SFN-induced changes in chromatin structure and composition. The SFN-mediated changes in levels of histone post-translational modifications, more specifically acetylation of histone H3 lysine 18 and di-methylation of histone H3 lysine 4, 2 modifications linked with high risk of prostate cancer recurrence, were associated with regulatory elements within the hTERT promoter region. Chromatin condensation may also play a role in SFN-mediated hTERT repression, since expression and recruitment of MeCP2, a known chromatin compactor, were altered in SFN treated prostate cancer cells. Chromatin immuno-precipitation (ChIP) of MeCP2 showed enrichment over regions of the hTERT promoter with increased nucleosome density. These combined results strongly support a role for SFN in the mediation of epigenetic events leading to the repression of hTERT in prostate cancer cells. This ability of SFN to modify chromatin composition and structure associated with target gene expression provides a new model by which dietary phytochemicals may exert their chemoprevention activity.
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Singh, Prashant, and Moray Campbell. "The Interactions of microRNA and Epigenetic Modifications in Prostate Cancer." Cancers 5, no. 4 (August 9, 2013): 998–1019. http://dx.doi.org/10.3390/cancers5030998.
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Wang, Hung-Jung, and Wen-Chi Cheng. "Current advances of targeting epigenetic modifications in neuroendocrine prostate cancer." Tzu Chi Medical Journal 33, no. 3 (2021): 224. http://dx.doi.org/10.4103/tcmj.tcmj_220_20.
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Adjakly, Mawussi, Marjolaine Ngollo, Aslihan Dagdemir, Gaëlle Judes, Amaury Pajon, Seher Karsli-Ceppioglu, Frédérique Penault-Llorca, et al. "Prostate cancer: The main risk and protective factors – Epigenetic modifications." Annales d'Endocrinologie 76, no. 1 (February 2015): 25–41. http://dx.doi.org/10.1016/j.ando.2014.09.001.
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Olumi, Aria F., Rongbin Ge, Zongwei Wang, Shulin Wu, Shahin Tabetabaei, and Chin-Lee Wu. "Regulation of steroid-5-alpha-reductase 2 (SRD5A2) in human prostate by epigenetic modifications." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 204. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.204.
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204 Background: 5-alpha reductase type 2 (SRD5A2), an enzyme that is critical for prostatic development and growth. We have found that many aging prostate tissues do not express the enzyme. We previously showed that expression of SRD5A2 is not static and epigenetic modulations by DNA methyltransferase and pro-inflammatory cytokines play important roles in silencing of SRD5A2. Here we wished to define the methylation pattern and identify specific CpG dinucleotides that are methylated in the SRD5A2promoter region. Methods: Ninety six prostate samples from patients were obtained by transurethral resection of prostate (TURP). Methylation of SRD5A2 promoter was assessed using Methylated CpG Island Recovery Assay (MIRA). Bisulfide conversion of Genomic DNA was performed using Epimark bisulfide conversion kit. Primers for bisulfide sequencing were designed using MethPrimer software and bisulfide sequencing was performed using 3730XL DNA Sequencers. Binding of histone demethylase to promoter DNA was analyzed by ChiP assay. Results: We randomly selected 3 TURP samples with methylated SRD5A2 promoters and 3 TURP samples with un-methylated SRD5A2 promoters, and then bisulfide conversion and sequencing were performed to verify the methylation pattern of CpG dinucleotides on SRD5A2 promoter. We found that bisulfide sequencing analysis of SRD5A2 promoter was consistent with MIRA analysis. To further analyze the mediators of SRD5A2 promoter region, we show that TNF-alpha up-regulates expression of Snail protein, which is a central regulator of both DNA methylation and histone methylation, and increases the binding of H3K9me to SRD5A2promoter region, but not H3K27me or H4K20me. Conclusions: Methylation of SRD5A2 promoter, which is regulated by DNMT1, proinflammatory cytokines and the histone methylase, H3K9me, accounts for suppression of SRD5A2 in many adult human prostate tissues. Bisulfide conversion and sequencing confirm and focus the specified CpG dinucleotides that are methylated enabling us to evaluate mechanisms and patterns of SRD5A2 promoter methylation in order to study the functional significance of SRD5A2 methylation. Grant support: NIH/R01 DK091353.
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Leal, Alessandro, David Sidransky, and Mariana Brait. "Tissue and Cell-Free DNA-Based Epigenomic Approaches for Cancer Detection." Clinical Chemistry 66, no. 1 (December 30, 2019): 105–16. http://dx.doi.org/10.1373/clinchem.2019.303594.
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Abstract BACKGROUND Over 9 million people die of cancer each year worldwide, reflecting the unmet need for effective biomarkers for both cancer diagnosis and prognosis. Cancer diagnosis is complex because the majority of malignant tumors present with long periods of latency and lack of clinical presentation at early stages. During carcinogenesis, premalignant cells experience changes in their epigenetic landscapes, such as differential DNA methylation, histone modifications, nucleosome positioning, and higher orders of chromatin changes that confer growth advantage and contribute to determining the biologic phenotype of human cancers. CONTENT Recent progress in microarray platforms and next-generation sequencing approaches has allowed the characterization of abnormal epigenetic patterns genome wide in a large number of cancer cases. The sizable amount of processed data also comes with challenges regarding data management and assessment for effective biomarker exploration to be further applied in prospective clinical trials. Epigenetics-based single or panel tests of genes are being explored for clinical management to fulfill unmet needs in oncology. The advance of these tests to the clinical routine will depend on rigorous, extensive, and independent validation in well-annotated cohort of patients and commercial development of clinical routine–friendly and adequate procedures. SUMMARY In this review we discuss the analytic validation of tissue and cell-free DNA-based epigenomic approaches for early cancer detection, diagnosis, and treatment monitoring and the clinical utility of candidate epigenetic alterations applied to colorectal, glioblastoma, breast, prostate, bladder, and lung cancer management.
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Godbole, Abhijit M., and Vincent C. O. Njar. "New Insights into the Androgen-Targeted Therapies and Epigenetic Therapies in Prostate Cancer." Prostate Cancer 2011 (2011): 1–13. http://dx.doi.org/10.1155/2011/918707.
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Prostate cancer is the most common cancer in men in the United States, and it is the second leading cause of cancer-related death in American men. The androgen receptor (AR), a receptor of nuclear family and a transcription factor, is the most important target in this disease. While most efforts in the clinic are currently directed at lowering levels of androgens that activate AR, resistance to androgen deprivation eventually develops. Most prostate cancer deaths are attributable to this castration-resistant form of prostate cancer (CRPC). Recent work has shed light on the importance of epigenetic events including facilitation of AR signaling by histone-modifying enzymes, posttranslational modifications of AR such as sumoylation. Herein, we provide an overview of the structure of human AR and its key structural domains that can be used as targets to develop novel antiandrogens. We also summarize recent findings about the antiandrogens and the epigenetic factors that modulate the action of AR.
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Kushwaha, Prem Prakash, and Sanjay Gupta. "New insights for drug resistance in metastatic castration-resistant prostate cancer." Cancer Drug Resistance 5, no. 4 (2022): 846–49. http://dx.doi.org/10.20517/cdr.2022.83.
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Prostate cancer is the most common cancer and is the second leading cause of cancer-related deaths among men in the United States. Androgen deprivation therapy (ADT) is the standard treatment for advanced-stage prostate cancer; however, this treatment eventually fails, leading to an incurable disease subtype known as metastatic castration-resistant prostate cancer (mCRPC). There are several molecular mechanisms that facilitate the development of mCRPC engaging androgen receptor (AR) growth axis, including AR amplification, gain of function AR mutations, and AR splice variants that are constitutively active and are a foremost factor for mCRPC development. AR-independent mechanisms with exceptionally low or absent AR expression found in cancer cells suppress ADT effectiveness and contribute to aggressive variants, including neuroendocrine differentiation. Several other AR regulatory factors such as epigenetic modification(s), and DNA damage response have been reported during post-ADT exposure and play a crucial role in mCRPC development. Therefore, targeting prostate cancer cells before their progression to mCRPC would improve patient outcomes. This special issue in “Cancer Drug Resistance” focuses on understanding the mechanism(s) and development of mCRPC resistance. This special issue also highlights the therapeutic strategies to combat against resistant subtype. This issue comprehensively reviews the mCRPC and delivers the update in the forum of mCRPC resistance development.
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Bhattacharya, Sreyashi, Ridwan Islam, Sanika Bodas, Juhi Mishra, Dipanwita Das, Kaustubh Datta, and Samikshan Dutta. "Abstract LB037: Chromatin modifications guide Pax5 dependent gene expression in NE like prostate cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB037. http://dx.doi.org/10.1158/1538-7445.am2022-lb037.
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Abstract Background: Prolonged ablation of androgen receptor pathway in prostate cancer leads to the emergence of therapy resistant neuroendocrine-like (NE-like) aggressive lineage. This NE development is associated with chromatin reprogramming underlying epigenetic alterations and changes in transcriptional network. Clinically, NE development follows a poorer progression with multifaceted therapeutic challenges. Current lack of effective understanding of this NE trans-differentiation process limits the stratification of therapeutic window with further worsened patient management. The following study aims to identify the sequential molecular players responsible for therapy resistant NE like development. Objective: The primary objective of this study is to understand how chromatin modifications along with epigenetic regulation dictates the establishment of NE trans-differentiation process in Prostate Cancer in response to Androgen Receptor blockade therapy. Methods: We generated various NE-like cell lines either by genetic modification or therapeutic selection. We performed RNA Seq, ATAC Seq and acetylated Histone (H3K18 and H3K27) ChIP Seq in our developed NE and adenocarcinoma cell lines. We next compared ATAC Seq and Acetylated histone ChIP Seq with RNA Seq in C4-2B and C4-2BER. Results: Our ATAC Seq and acetylated histone footprints (Ac H3K18 and Ac H3K27 ChIP Seq) analyses revealed an enhanced chromatin accessibility during adenocarcinoma to NE transformation. Overlapping RNA seq results further suggested newly transcribed neuronal genes with higher degrees of promoter accessibility. Transcription Factor scanning analysis among newly active gene promoters revealed preferential binding of Pax5, whose expression has been validated to be selectively occurring in NE lineage unlike adenocarcinoma. Further analysis of Pax5 promoter site suggested that changes in 5-hydroxymethylation pattern during adenocarcinoma to NE transformation guided the recruitment of PBX1 at Pax5 promoter. Validating NE patient expression in silico supported that PBX1/Pax5 expressions are selective in NE lineage development. Conclusions: Our study concludes that specific chromatin alterations guide the recruitment of PBX1 to upregulate Pax5 to maintain a therapy resistant neuronal surrounding in NE-like prostate cancer development. Citation Format: Sreyashi Bhattacharya, Ridwan Islam, Sanika Bodas, Juhi Mishra, Dipanwita Das, Kaustubh Datta, Samikshan Dutta. Chromatin modifications guide Pax5 dependent gene expression in NE like prostate cancer [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 LB037.
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Hightower, Alexandria J., Suhn K. Rhie, Sara M. Falzarano, and Sarah Buxbaum. "Abstract C045: Investigating molecular and genetic contributions to racial disparities in prostate cancer by integrating multi-omic datasets available in public." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): C045. http://dx.doi.org/10.1158/1538-7755.disp22-c045.
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Abstract African-American males are disproportionately affected by prostate cancer in comparison to other racial and ethnic groups. African-American males have increased risk for the disease, experience higher incidence and mortality rates, and present higher grade and stage prostate tumors than Caucasian men. To determine molecular mechanisms beyond racial disparities in prostate cancer, molecular and genetic profiles of prostate tumor samples from different ethnic groups are developed. For example, DNA sequencing in the form of target-based array or whole exome and genome sequencing revealed SNPs, genetic mutations, deletions, and amplifications linked to prostate cancer subgroups. Comparative analysis of DNA sequences of prostate cancer cells have pinpointed areas of interest that suggest race specific mutations. Moreover, differentially expressed genes between prostate tumor tissue samples from African and Caucasian ancestries are identified using RNA sequencing and microarray-based methods. Abnormal levels of gene expression are measured by the levels of mRNA. Furthermore, epigenetic modifications, such as DNA methylation levels were examined, identifying CpG sites that are differentially methylated among ethnic groups. To comprehensively examine molecular and genetic contributions to racial disparities in prostate cancer, we compiled over 200 published studies that profiled genome, epigenome, and transcriptome in prostate tumor tissues from diverse ethnic groups. Specifically, we categorized studies according to their method and organized the identified features that offer insight into racial disparities in prostate cancer. For instance, we reviewed over 100 studies that identify reproducible genetic alterations found in prostate cancer patients from African ancestry from DNA sequencing experiments. We also reviewed over 50 studies that utilized RNA sequencing to measure gene expression levels in prostate tumor tissues from African-American male samples, identifying genes and signaling pathways abnormally dysregulated in the disease. In addition, we reviewed over 25 studies quantifying epigenetic modifications to determine key and reproducible epigenetic alterations linked to aggressiveness of the disease from African American. Subsequently, we identified socioeconomic factors that are associated with molecular features contributing to the increased risk for prostate cancer in African-American men. Overall, we evaluated multiple molecular and genetic features that contribute to racial disparities in prostate cancer. This may provide researchers with valuable background knowledge and perspective for identifying biomarkers for specific prostate cancer subgroups. Citation Format: Alexandria J. Hightower, Suhn K. Rhie, Sara M. Falzarano, Sarah Buxbaum. Investigating molecular and genetic contributions to racial disparities in prostate cancer by integrating multi-omic datasets available in public [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C045.
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Osterman, Carlos J. Diaz, Anders Berglund, Shannalee Martinez, Camila Luis, Julie Dutil, Jaime Matta, Jarline Encarnacion-Medina, et al. "Abstract 3675: Epigenetic variations associated with therapy resistance among prostate tumors from Puerto Rican men." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3675. http://dx.doi.org/10.1158/1538-7445.am2022-3675.
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Abstract Prostate cancer (PCa) is the leading cause of cancer-related death in Puerto Rican (PR) men, a population at higher risk of developing the disease than other Hispanic/Latino groups. But the relationship between this phenomenon and epigenetics, and how this relationship explains PCa racial and ethnic health disparities are controversial. The purpose of this study was to expand on the knowledge regarding epigenetic differences in terms of DNA methylation to enable risk stratification and treatment selection in this genetically admixed population. In addition, we aim to assess differential DNA methylation patterns associated with drug resistance in PCa in PR Hispanic/Latino men. Since epigenetic changes and modifications represent critical components of carcinogenesis and progression, we are expecting differential methylation levels between aggressive vs. indolent, and resistant vs. non-resistant cases. Prostate tumors from PR men were stratified based on Gleason score. Methylation levels were measured by Illumina Infinium Methylation EPIC BeadChip DNA methylation platform, and bioinformatic analyses. In parallel, DNA methylation profiles were also analyzed using genomic DNA from PCa cells selected for resistance to androgen depletion, enzalutamide resistance, or docetaxel resistance. We identified 1,225 differentially methylated genes in prostate tumors compared with normal adjacent tissues, and 141 differentially methylated genes between aggressive vs. indolent tumors. Additionally, 723 differentially methylated genes were found in therapy resistant cell lines compared to parental controls. Analysis of the methylated genes obtained from aggressive prostate tumors from Puerto Rican patients and therapy-resistant PCa cell lines revealed four overlapping methylated genes: RNF220, FAM65B, PRDM16, and DGKH. Further analysis of PCa cells resistant to androgen depletion, enzalutamide, or docetaxel demonstrated impaired cellular migration of resistant phenotypes upon DNA methyltransferase (DNMT) inhibition using 5-azacytidine or zebularine compared to parental cell lines. DNMT1 was associated with resistance in PCa cell lines, and future studies will include silencing of methyltransferases will evaluation of drug re-sensitization. These findings provide critical insight into the epigenetic landscape of aggressive prostate tumors among PR men and highlight several candidate methylation biomarkers for assessing risk in this population. Citation Format: Carlos J. Diaz Osterman, Anders Berglund, Shannalee Martinez, Camila Luis, Julie Dutil, Jaime Matta, Jarline Encarnacion-Medina, Carmen Ortiz-Sanchéz, Liang Wang, Jasreman Dhillon, Youngchul Kim, Hyun Y. Park, Gilbert Ruiz-Deya, Kosj Yamoah, Jong Y. Park. Epigenetic variations associated with therapy resistance among prostate tumors from Puerto Rican men [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 3675.
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Kawamoto, Ken, Steven T. Okino, Robert F. Place, Shinji Urakami, Hiroshi Hirata, Nobuyuki Kikuno, Toshifumi Kawakami, et al. "Epigenetic Modifications of RASSF1A Gene through Chromatin Remodeling in Prostate Cancer." Clinical Cancer Research 13, no. 9 (May 1, 2007): 2541–48. http://dx.doi.org/10.1158/1078-0432.ccr-06-2225.
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Nowacka-Zawisza, Maria, and Ewelina Wiśnik. "DNA methylation and histone modifications as epigenetic regulation in prostate cancer." Oncology Reports 38, no. 5 (September 20, 2017): 2587–96. http://dx.doi.org/10.3892/or.2017.5972.
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Pasic, Maria D., Ekaterina Olkhov, Bharati Bapat, and George M. Yousef. "Epigenetic regulation of kallikrein-related peptidases: there is a whole new world out there." Biological Chemistry 393, no. 5 (May 1, 2012): 319–30. http://dx.doi.org/10.1515/hsz-2011-0273.
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AbstractThe human kallikreins are a cluster of 15 kallikreins and kallikrein-related peptidases (KLKs). Evidence shows the involvement of KLKs in a wide range of pathophysiological processes, and underscores their potential contribution to cancer, skin and neurodegenerative disorders. The control ofKLKexpression is not fully elucidated. Understanding the mechanisms controllingKLKexpression is an essential step towards exploring the pathogenesis of several diseases and the use of KLKs as disease biomarkers and/or therapeutic targets. Recently, epigenetic changes (including methylation, histone modification and microRNAs [miRNAs]) have drawn attention as a new dimension for controllingKLKexpression. Reports showed the effect of methylation on the expression ofKLKgenes. This was also shown to have potential utility as a prognostic marker in cancer. miRNAs are small RNAs that control the expression of their targets at the post-transcriptional level. Target prediction showed that KLKs are potential targets of miRNAs that are dysregulated in tumors, including prostate, kidney and ovarian cancers, with downstream effect on tumor proliferation. Experimental validation remains an essential step to confirm the KLK-miRNA interaction. Epigenetic regulation of KLKs holds promise for an array of therapeutic applications in many diseases including cancer.
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Martin, Francis L. "Epigenetic Influences in the Aetiology of Cancers Arising from Breast and Prostate: A Hypothesised Transgenerational Evolution in Chromatin Accessibility." ISRN Oncology 2013 (February 3, 2013): 1–13. http://dx.doi.org/10.1155/2013/624794.
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Epidemiological studies have consistently supported the notion that environmental and/or dietary factors play a central role in the aetiology of cancers of the breast and prostate. However, for more than five decades investigators have failed to identify a single cause-and-effect factor, which could be implicated; identification of a causative entity would allow the implementation of an intervention strategy in at-risk populations. This suggests a more complex pathoaetiology for these cancer sites, compared to others. When one examines the increases or decreases in incidence of specific cancers amongst migrant populations, it is notable that disease arising in colon or stomach requires one or at most two generations to exhibit a change in incidence to match that of high-incidence regions, whereas for breast or prostate cancer, at least three generations are required. This generational threshold could suggest a requirement for nonmutation-driven epigenetic alterations in the F0/F1 generations (parental/offspring adopting a more westernized lifestyle), which then predisposes the inherited genome of subsequent generations to mutagenic/genotoxic alterations leading to the development of sporadic cancer in these target sites. As such, individual susceptibility to carcinogen insult would not be based per se on polymorphisms in activating/detoxifying/repair enzymes, but on elevated accessibility of crucial target genes (e.g., oncogenes, tumour suppressor genes) or hotspots therein to mutation events. This could be termed a genomic susceptibility organizational structure (SOS). Several exposures including alcohol and heavy metals are epigens (i.e., modifiers of the epigenome), whereas others are mutagenic/genotoxic, for example, heterocyclic aromatic amines; humans are continuously and variously exposed to mixtures of these agents. Within such a transgenerational multistage model of cancer development, determining the interaction between epigenetic modification to generate a genomic SOS and genotoxic insult will facilitate a new level of understanding in the aetiology of cancer.
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Gonye, Anna, Chi-Ju Kim, Ken Pienta, and Sarah Amend. "Abstract A028: Investigating the epigenetic landscape of chemotherapy-induced polyaneuploid prostate cancer cells." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): A028. http://dx.doi.org/10.1158/1538-7445.cancepi22-a028.
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Abstract While localized prostate cancer (PCa) has a high treatment success rate, over 30,000 individuals in the United States and 350,000 men globally die each year from therapy resistant, metastatic PCa. A thorough understanding of the factors contributing to PCa recurrence following development of therapy resistance is acutely needed in order to develop efficacious treatments and disease-management strategies. Our group and others have identified a unique minority population of physically enlarged cancer cells with polyaneuploid genomes, termed polyaneuploid cancer cells (PACCs), in the tumors of patients with metastatic prostate cancer and in other tumor types. PACCs are the result of a polyaneuploid transition that occurs when aneuploid cancer cells experience environmental or therapeutic stress. These aneuploid cancer cells then pause their cell cycle after whole genome doubling to survive the environmental insult. Cancer cells in the PACC state appear to be quiescent and have an increased capacity for invasion/motility, an ability to endure in stressful or novel environments, and a propensity to undergo depolyploidization to re-establish the cancer cell population. We hypothesize that PACCs are critical players in prostate cancer therapy resistance and recurrence. We seek to better understand the life cycle of the PACC state in PCa in order to inform the design of new therapeutic strategies that prevent disease recurrence. Our data suggests that PCa cells in the PACC state tend to have a large polyploid single nucleus more frequently than multiple smaller, single nuclei, though both are observed at all timepoints in PACC recovery. Nuclear morphology and size certainly will impact the way that a cell organizes and utilizes its genome. Additionally, genome organization and stability have been demonstrated to be important factors/drivers of cancer development, progression, and recurrence. Importantly, epigenetic changes such as histone modifications can drastically affect chromatin condensation, which subsequently can alter the gene accessibility and transcription profile of a cell. We hypothesize that cancer cells in the PACC state have different histone modifications and different regions of accessible chromatin compared to parental cancer cells, and that these differences will also impact the gene expression of PACCs. Citation Format: Anna Gonye, Chi-Ju Kim, Ken Pienta, Sarah Amend. Investigating the epigenetic landscape of chemotherapy-induced polyaneuploid prostate cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A028.
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Taverna, Gianluigi, Mauro Seveso, Guido Giusti, Rodolfo Hurle, Pierpaolo Graziotti, Sanja Štifter, Maurizio Chiriva-Internati, and Fabio Grizzi. "Senescent Remodeling of the Innate and Adaptive Immune System in the Elderly Men with Prostate Cancer." Current Gerontology and Geriatrics Research 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/478126.
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Despite years of intensive investigation that has been made in understanding prostate cancer, it remains a major cause of death in men worldwide. Prostate cancer emerges from multiple alterations that induce changes in expression patterns of genes and proteins that function in networks controlling critical cellular events. Based on the exponential aging of the population and the increasing life expectancy in industrialized Western countries, prostate cancer in the elderly men is becoming a disease of increasing significance. Aging is a progressive degenerative process strictly integrated with inflammation. Several theories have been proposed that attempt to define the role of chronic inflammation in aging including redox stress, mitochondrial damage, immunosenescence, and epigenetic modifications. Here, we review the innate and adaptive immune systems and their senescent remodeling in elderly men with prostate cancer.
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Dalpatraj, Nidhi, Ankit Naik, and Noopur Thakur. "Combination Treatment of a Phytochemical and a Histone Demethylase Inhibitor—A Novel Approach towards Targeting TGFβ-Induced EMT, Invasion, and Migration in Prostate Cancer." International Journal of Molecular Sciences 24, no. 3 (January 17, 2023): 1860. http://dx.doi.org/10.3390/ijms24031860.
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Minimizing side effects, overcoming cancer drug resistance, and preventing metastasis of cancer cells are of growing interest in current cancer therapeutics. Phytochemicals are being researched in depth as they are protective to normal cells and have fewer side effects. Hesperetin is a citrus bioflavonoid known to inhibit TGFβ-induced epithelial-to-mesenchymal transition (EMT), migration, and invasion of prostate cancer cells. Targeting epigenetic modifications that cause cancer is another class of upcoming therapeutics, as these changes are reversible. Global H3K27me3 levels have been found to be reduced in invasive prostate adenocarcinomas. Combining a demethylase inhibitor and a known anti-cancer phytochemical is a unique approach to targeting cancer to attain the aforementioned objectives. In the current study, we used an H3K27 demethylase (JMJD3/KDM6B) inhibitor to study its effects on TGFβ-induced EMT in prostate cancer cells. We then gave a combined hesperetin and GSK-J4 treatment to the PC-3 and LNCaP cells. There was a dose-dependent increase in cytotoxicity and inhibition of TGFβ-induced migration and invasion of prostate cancer cells after GSK-J4 treatment. GSK-J4 not only induced trimethylation of H3K27 but also induced the trimethylation of H3K4. Surprisingly, there was a reduction in the H3K9me3 levels. GSK-J4 alone and a combination of hesperetin and GSK-J4 treatment effectively inhibit the important hallmarks of cancer, such as cell proliferation, migration, and invasion, by altering the epigenetic landscape of cancer cells.
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SABHERWAL, YAMINI, NITIN MAHAJAN, and MING ZHANG. "Epigenetic modifications of prostate-derived Ets transcription factor in breast cancer cells." Oncology Reports 30, no. 4 (August 6, 2013): 1985–88. http://dx.doi.org/10.3892/or.2013.2661.
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Kawamoto, Ken, Steven T. Okino, Robert Place, Shinji Urakami, Hiroshi Hirata, Nobuyuki Kikuno, Toshifumi Kawakami, et al. "542: Epigenetic Modifications of RASSF1A Gene Through Chromatin Remodeling in Prostate Cancer." Journal of Urology 177, no. 4S (April 2007): 181. http://dx.doi.org/10.1016/s0022-5347(18)30782-1.
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Jurkovicova, Dana, Christiana M. Neophytou, Ana Čipak Gašparović, and Ana Cristina Gonçalves. "DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities." International Journal of Molecular Sciences 23, no. 23 (November 24, 2022): 14672. http://dx.doi.org/10.3390/ijms232314672.
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Resistance to chemo- and radiotherapy is a common event among cancer patients and a reason why new cancer therapies and therapeutic strategies need to be in continuous investigation and development. DNA damage response (DDR) comprises several pathways that eliminate DNA damage to maintain genomic stability and integrity, but different types of cancers are associated with DDR machinery defects. Many improvements have been made in recent years, providing several drugs and therapeutic strategies for cancer patients, including those targeting the DDR pathways. Currently, poly (ADP-ribose) polymerase inhibitors (PARP inhibitors) are the DDR inhibitors (DDRi) approved for several cancers, including breast, ovarian, pancreatic, and prostate cancer. However, PARPi resistance is a growing issue in clinical settings that increases disease relapse and aggravate patients’ prognosis. Additionally, resistance to other DDRi is also being found and investigated. The resistance mechanisms to DDRi include reversion mutations, epigenetic modification, stabilization of the replication fork, and increased drug efflux. This review highlights the DDR pathways in cancer therapy, its role in the resistance to conventional treatments, and its exploitation for anticancer treatment. Biomarkers of treatment response, combination strategies with other anticancer agents, resistance mechanisms, and liabilities of treatment with DDR inhibitors are also discussed.
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Day, Tanya K., and Tina Bianco-Miotto. "Common gene pathways and families altered by DNA methylation in breast and prostate cancers." Endocrine-Related Cancer 20, no. 5 (July 1, 2013): R215—R232. http://dx.doi.org/10.1530/erc-13-0204.
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Epigenetic modifications, such as DNA methylation, are widely studied in cancer as they are stable and easy to measure genome wide. DNA methylation changes have been used to differentiate benign from malignant tissue and to predict tumor recurrence or patient outcome. Multiple genome wide DNA methylation studies in breast and prostate cancers have identified genes that are differentially methylated in malignant tissue compared with non-malignant tissue or in association with hormone receptor status or tumor recurrence. Although this has identified potential biomarkers for diagnosis and prognosis, what is highlighted by reviewing these studies is the similarities between breast and prostate cancers. In particular, the gene families/pathways targeted by DNA methylation in breast and prostate cancers have significant overlap and include homeobox genes, zinc finger transcription factors, S100 calcium binding proteins, and potassium voltage-gated family members. Many of the gene pathways targeted by aberrant methylation in breast and prostate cancers are not targeted in other cancers, suggesting that some of these targets may be specific to hormonal cancers. Genome wide DNA methylation profiles in breast and prostate cancers will not only define more specific and sensitive biomarkers for cancer diagnosis and prognosis but also identify novel therapeutic targets, which may be direct targets of agents that reverse DNA methylation or which may target novel gene families that are themselves DNA methylation targets.
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Naik, Ankit, Nidhi Dalpatraj, and Noopur Thakur. "Global Histone H3 Lysine 4 Trimethylation (H3K4me3) Landscape Changes in Response to TGFβ." Epigenetics Insights 14 (January 2021): 251686572110517. http://dx.doi.org/10.1177/25168657211051755.
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TGFβ expression acts as a biomarker of poor prognosis in prostate cancer. It plays a dual functional role in prostate cancer. In the early stages of the tumor, it acts as a tumor suppressor while at the later stages of tumor development, it promotes metastasis. The molecular mechanisms of action of TGFβ are largely understood through the canonical and non-canonical signal transduction pathways. Our understanding of the mechanisms that establish transient TGFβ stimulation into stable gene expression patterns remains incomplete. Epigenetic marks like histone H3 modifications are directly linked with gene expression and they play an important role in tumorigenesis. In this report, we performed chromatin immunoprecipitation-sequencing (ChIP-Seq) to identify the genome-wide regions that undergo changes in histone H3 Lysine 4 trimethylation (H3K4me3) occupancy in response to TGFβ stimulation. We also show that TGFβ stimulation can induce acute epigenetic changes through the modulation of H3K4me3 signals at genes belonging to special functional categories in prostate cancer. TGFβ induces the H3K4me3 on its own ligands like TGFβ, GDF1, INHBB, GDF3, GDF6, BMP5 suggesting a positive feedback loop. The majority of genes were found to be involved in the positive regulation of transcription from the RNA polymerase II promoter in response to TGFβ. Other functional categories were intracellular protein transport, brain development, EMT, angiogenesis, antigen processing, antigen presentation via MHC class II, lipid transport, embryo development, histone H4 acetylation, positive regulation of cell cycle arrest, and genes involved in mitotic G2 DNA damage checkpoints. Our results link TGFβ stimulation to acute changes in gene expression through an epigenetic mechanism. These findings have broader implications on epigenetic bases of acute gene expression changes caused by growth factor stimulation.
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Kawamoto, Ken, Steven T. Okino, Robert F. Place, Shinji Urakami, Hiroshi Hirata, Nobuyuki Kikuno, Toshifumi Kawakami, et al. "Editor's Note: Epigenetic Modifications of RASSF1A Gene through Chromatin Remodeling in Prostate Cancer." Clinical Cancer Research 27, no. 9 (May 1, 2021): 2665. http://dx.doi.org/10.1158/1078-0432.ccr-21-0847.
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Henrique, Rui, Ana Oliveira, Vera L. Costa, Tiago Baptista, Ana Martins, António Morais, Jorge Oliveira, and Carmen Jerónimo. "Epigenetic regulation of MDR1 gene through post-translational histone modifications in prostate cancer." BMC Genomics 14, no. 1 (2013): 898. http://dx.doi.org/10.1186/1471-2164-14-898.
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Saraç, H., O. D. Toparlak, A. Kaplan, A. Ebrahimi, T. Bagci-Önder, T. Onder, and N. A. Lack. "414: Epigenetic modifications of androgen receptor signaling in castration resistant prostate cancer (CRPC)." European Journal of Cancer 50 (July 2014): S99. http://dx.doi.org/10.1016/s0959-8049(14)50369-3.
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Kushwaha, Prem Prakash, Shiv Verma, Shashank Kumar, and Sanjay Gupta. "Role of prostate cancer stem-like cells in the development of antiandrogen resistance." Cancer Drug Resistance 5, no. 2 (2022): 459–71. http://dx.doi.org/10.20517/cdr.2022.07.
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Androgen deprivation therapy (ADT) is the standard of care treatment for advance stage prostate cancer. Treatment with ADT develops resistance in multiple ways leading to the development of castration-resistant prostate cancer (CRPC). Present research establishes that prostate cancer stem-like cells (CSCs) play a central role in the development of treatment resistance followed by disease progression. Prostate CSCs are capable of self-renewal, differentiation, and regenerating tumor heterogeneity. The stemness properties in prostate CSCs arise due to various factors such as androgen receptor mutation and variants, epigenetic and genetic modifications leading to alteration in the tumor microenvironment, changes in ATP-binding cassette (ABC) transporters, and adaptations in molecular signaling pathways. ADT reprograms prostate tumor cellular machinery leading to the expression of various stem cell markers such as Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1), Prominin 1 (PROM1/CD133), Indian blood group (CD44), SRY-Box Transcription Factor 2 (Sox2), POU Class 5 Homeobox 1(POU5F1/Oct4), Nanog and ABC transporters. These markers indicate enhanced self-renewal and stemness stimulating CRPC evolution, metastatic colonization, and resistance to antiandrogens. In this review, we discuss the role of ADT in prostate CSCs differentiation and acquisition of CRPC, their isolation, identification and characterization, as well as the factors and pathways contributing to CSCs expansion and therapeutic opportunities.
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Costea, Teodora, Oana Cezara Vlad, Luminita-Claudia Miclea, Constanta Ganea, János Szöllősi, and Maria-Magdalena Mocanu. "Alleviation of Multidrug Resistance by Flavonoid and Non-Flavonoid Compounds in Breast, Lung, Colorectal and Prostate Cancer." International Journal of Molecular Sciences 21, no. 2 (January 8, 2020): 401. http://dx.doi.org/10.3390/ijms21020401.
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The aim of the manuscript is to discuss the influence of plant polyphenols in overcoming multidrug resistance in four types of solid cancers (breast, colorectal, lung and prostate cancer). Effective treatment requires the use of multiple toxic chemotherapeutic drugs with different properties and targets. However, a major cause of cancer treatment failure and metastasis is the development of multidrug resistance. Potential mechanisms of multidrug resistance include increase of drug efflux, drug inactivation, detoxification mechanisms, modification of drug target, inhibition of cell death, involvement of cancer stem cells, dysregulation of miRNAs activity, epigenetic variations, imbalance of DNA damage/repair processes, tumor heterogeneity, tumor microenvironment, epithelial to mesenchymal transition and modulation of reactive oxygen species. Taking into consideration that synthetic multidrug resistance agents have failed to demonstrate significant survival benefits in patients with different types of cancer, recent research have focused on beneficial effects of natural compounds. Several phenolic compounds (flavones, phenolcarboxylic acids, ellagitannins, stilbens, lignans, curcumin, etc.) act as chemopreventive agents due to their antioxidant capacity, inhibition of proliferation, survival, angiogenesis, and metastasis, modulation of immune and inflammatory responses or inactivation of pro-carcinogens. Moreover, preclinical and clinical studies revealed that these compounds prevent multidrug resistance in cancer by modulating different pathways. Additional research is needed regarding the role of phenolic compounds in the prevention of multidrug resistance in different types of cancer.
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Palicelli, Andrea, Stefania Croci, Alessandra Bisagni, Eleonora Zanetti, Dario De Biase, Beatrice Melli, Francesca Sanguedolce, et al. "What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1." International Journal of Molecular Sciences 22, no. 22 (November 15, 2021): 12314. http://dx.doi.org/10.3390/ijms222212314.
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Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.
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Chen, Hong, Szu-wei Tu, and Jer-Tsong Hsieh. "Down-regulation of Human DAB2IP Gene Expression Mediated by Polycomb Ezh2 Complex and Histone Deacetylase in Prostate Cancer." Journal of Biological Chemistry 280, no. 23 (April 6, 2005): 22437–44. http://dx.doi.org/10.1074/jbc.m501379200.
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Human DAB2IP (hDAB2IP), a novel GTPase-activating protein modulating the Ras-mediated signaling and tumor necrosis factor-mediated apoptosis, is a potent growth inhibitor in human prostate cancer (PCa). Loss of hDAB2IP expression in PCa is due to altered epigenetic regulation (i.e. DNA methylation and histone modification) of its promoter region. The elevated polycomb Ezh2, a histone methyltransferase, has been associated with PCa progression. In this study, we have demonstrated that an increased Ezh2 expression in normal prostatic epithelial cells can suppress hDAB2IP gene expression. In contrast, knocking down the endogenous Ezh2 levels in PCa by a specific small interfering RNA can increase hDAB2IP expression. The association of Ezh2 complex (including Eed and Suz12) with hDAB2IP gene promoter is also detected in PCa cells but not in normal prostatic epithelial cells. Increased Ezh2 expression in normal prostatic epithelial cells by cDNA transfection facilitates the recruitment of other components of Ezh2 complex to the hDAB2IP promoter region accompanied with the increased levels of methyl histone H3 (H3) and histone deacetylase (HDAC1). Consistently, data from PCa cells transfected with Ezh2 small interfering RNA demonstrated that reduced Ezh2 levels resulted in the dissociation of Ezh2 complex accompanied with decreased levels of both methyl H3 and HDAC1 from hDAB2IP gene promoter. We further unveiled that the methylation status of Lys-27 but not Lys-9 of H3 in hDAB2IP promoter region is consistent with the hDAB2IP levels in both normal prostatic epithelial cells and PCa cells. Together, we conclude that hDAB2IP gene is a target gene of Ezh2 in prostatic epithelium, which provides an underlying mechanism of the down-regulation of hDAB2IP gene in PCa.
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Gopal, Srila, Amanda Creech, Adam Officer, Shawn Egri, Desiree Davison, Jacob D. Jaffe, and Iris Z. Jaffe. "The Impact of Chemotherapeutic Agents on Signaling and Epigenetics in Vascular Endothelial Cells." Blood 128, no. 22 (December 2, 2016): 1353. http://dx.doi.org/10.1182/blood.v128.22.1353.1353.
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Abstract Background: Molecularly targeted anti-cancer therapeutics have revolutionized cancer treatment. However, cardiovascular toxicity is often a dose limiting side effect of these targeted agents. Vascular toxicities include hypertension, increased cardiovascular ischemic events and increased risk of arterial and venous thrombosis. The mechanisms of vascular toxicities are unclear and may be related to on or off target effects in vascular cells. Hypothesis: We hypothesize that small molecule kinase inhibitors cause off target phosphorylation in vascular endothelial cells some of which result in long-term epigenetic changes in histones and that epigenetic modulators also have long-term impact on vascular cell histone modifications. Methods and Results: To test this hypothesis, we used two novel, global, unbiased, high throughput proteomic assays to determine the phospho-signaling (P100 assay) and histone modification profiles (global chromatin profiling (GCP) assay) of human umbilical vein endothelial cells (HUVEC) treated with 26 drugs. The drug panel included 8 epigenetic modulators (vorinostat, decitabine, JQ1-s, GSK126, UNC 0646, GSK J4, resveratrol, geldanamycin), 9 kinase inhibitors (pazopanib, nilotinib, LY-294002, okadaic acid, tofacitinib, SP600125, losmapimod, ARA014418, staurosporine) and 9 other drugs (tretnoin, tacrolimus, sirolimus, lenalidomide, curcumin, KN-62, pravastatin, rolipram, dexamethasone).The proteomic assays were developed as part of the LINCS (Library of Integrated Network-Based Cellular Signatures) program at the Broad Institute. The P100 assay is a mass spectrometry-based targeted proteomics assay that detects and quantifies a representative set of 100 phosphopeptides that are present in a wide range of cell types and from which 1000 unique phosphosites may be imputed. The global chromatin profiling (GCP) is a novel mass spectrometry assay to simultaneously quantify over 70 histone modifications including phosphorylation, ubiquitination, methylation and acetylation. HUVECs cultured in 100 mm plates were treated in triplicate with each drug. After 3 hours, phosphopeptides were collected for the P100 assay and after 24 hours of treatment, histones were extracted for the GCP assay. For each assay, the peptides were mixed with a set of isotopically labeled internal standards and mass spectrometry was performed to quantify each phospho-peptide or modified histone peptide compared to the universal standard. We successfully treated and harvested cells under all proposed conditions above for both assays and mass spectrometry analysis for P-100 assay is underway and completed for GCP assay.We were able to visualize global changes to the histone epigenome in human endothelial cells in response to multiple pertubations for the first time. We found that most kinase inhibitors cause distinct histone epigenetic profiles in HUVECs, indicating more long term effects on vascular cells in addition to short term effects that are expected due to inhibition of specific kinases. We also compared the histone profile obtained in HUVECs to that of several cancer cell lines treated with the same drugs including MCF7 (breast), A549 (lung), A375 (skin) and PC3 (prostate).Some of these changes in histone marks seen in vascular cells are similar to those seen in cancer cells lines, while others are unique to endothelial cells. As predicted, the epigenetic modulators cause histone epigenetic changes in HUVECs. Interestingly, epigenetic modulators that do not directly inhibit enzymes affecting histone modifications (such DNA methylators and demethylators) also cause distinct histone epigenetic signatures in HUVECs. Conclusions: Small molecule anti-cancer agents alter the post-translational modifications present on histones of endothelial cells. In addition to histone changes expected from known epigenetic modulators, kinase inhibitors also produce distinct histone epigenetic signatures in endothelial cells, possibly the result of long term changes caused by target kinase inhibition. Further studies directed at specific histone epigenetic changes could identify critical signaling pathways in endothelial cells and also identify possible mechanisms of vascular toxicities of targeted agents. Disclosures No relevant conflicts of interest to declare.
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Vatanmakanian, Mousa, Sweaty Koul, Thangavel Chellappagounder, and Hari K. Koul. "Abstract A081: Epigenetic regulation of SPDEF gene in RCC7/T cells, a line of malignant African-American prostate epithelial cells." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): A081. http://dx.doi.org/10.1158/1538-7755.disp22-a081.
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Abstract Background: Prostate cancer (PCa) in African American (AA) men has an earlier onset, more aggressiveness with higher metastasis and mortality rate than in Caucasian men. SAM-pointed domain-containing Ets-like factor (SPDEF) has been identified as a possible suppressor of metastasis in castration-resistant prostate cancer (CRPC) in earlier investigations. Ongoing studies in our lab are focused on deciphering the role of SPDEF in PCa progression and metastasis with special emphasis on PCa in AA men. We discovered that SPDEF expression is lost in RCC7/T cells, and re-expression of SPDEF limits metastatic properties of these cells, however, the regulatory mechanisms underlying the loss of SPDEF have not been elucidated. In the current study, we investigated the role of epigenetic modulators (DNA methylation and histone modifications) in driving the loss of SPDEF. Methods: We analyzed publicly available data sets from TCGA (GDC TCGA Prostate Cancer, and TCGA Prostate Cancer (PRAD) for DNA methylation using Xena UCSC genome browser (https://xena.ucsc.edu/). We also analyzed histone ChIP-seq data from PCa cell lines using cistrome project (http://cistrome.org/db/#/). RCC7/T cells were grown in DMEM and maintained at 37°C in a humidified incubator. We used bisulfite sequencing (BSP) to examine DNA methylation in SPDEF gene in SPDEF proficient (LNCaP) and deficient (RCC7/T) cells. We also employed the ChIP-qPCR to reveal the active and repressive key histone marks (H3K4me3, H3K27ac, and H3K27me3) across the SPDEF gene. Results: In the clinical cohorts, SPDEF expression showed an inverse correlation with the degree of DNA methylation and expression of the epigenetic writer enzymes such as DNMT1 and EZH2. Our results revealed that the CpG islands in SPDEF gene are hyper-methylated in RCC7/T cells compared to LNCaP cells. Our analysis of the data from the cistrome project revealed an elevated enhancer repressive mark H3K27me3 (marked by EZH2) and a decreased promoter active mark, H3K4me3, in PC3 cells as compared with less metastatic LNCaP cells. Our results from ChIP-qPCR confirmed these findings. Moreover, we observed the methylation profiles in RCC7/T cells were similar to those of PC3 cells. Additionally, combination treatment with 5-aza-2-deoxycytidine (DNMT inhibitor) and GSK-126 (EZH2 inhibitor) increased the PDEF expressions levels and also restricted colony formation, migration and invasion in RCC7/T cells. Conclusion: Overall, these findings reveal an inverse correlation between expression of epigenetic writers (DNMT1 and EZH2) and SPDEF expression in PCa. Our results also suggest that SPDEF expression in PCa is regulated in part by epigenetic modifications, and that combined inhibition of DNMT1 and EZH2 may offer a therapeutic benefit in subsets of PCa patients including in AA men. Acknowledgements: These studies were funded in part by NIH/NCI-7R01CA242839 (HK) and unrestricted funds from the LSU-LCMC Cancer Center, School of Medicine -LSUHSC, New Orleans (HK). Grateful to LCU-LCMC Genomics core for DNA sequencing Citation Format: Mousa Vatanmakanian, Sweaty Koul, Thangavel Chellappagounder, Hari K. Koul. Epigenetic regulation of SPDEF gene in RCC7/T cells, a line of malignant African-American prostate epithelial cells [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A081.
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Brown, LaKendria K., Guoliang Li, Thanigaivelan Kanagasabai, and Zhenbang Chen. "Abstract 2962: The oncogenic role of epigenetic factor, SNF2L in PCa." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2962. http://dx.doi.org/10.1158/1538-7445.am2022-2962.
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Abstract Prostate cancer (PCa) is the second-leading cause of cancer mortality in the United States and is the most commonly diagnosed malignancy in African American men. Epigenetic regulation including chromatin remodeling plays a crucial role in the development and progression of many human diseases such as cancers. Epigenetic alterations contribute to the development and progression of PCa. These alterations may cause drug resistance to readily available treatment options for human cancers including PCa. Nucleosome-remodeling factor (NURF) consists of bromodomain-PHD finger transcription factor (BPTF), sucrose non-fermenting-2-like (SNF2L), and pRBAP46/48, controls the chromatin remodeling machinery. One of NURF’s major function is to regulate histone modifications and gene expression. Epigenetic factor, SNF2L, serves as the energy transducing subunit in NURF and is encoded by the SMARCA1 gene. SNF2L is a ubiquitously expressed transcription activator and its elevation is associated with cancer development. However, the role of SNF2L on PCa progression is still elusive. Therefore, there are unmet needs to understand the role of SNF2L in PCa in order to develop effective therapeutic approaches of controlling this malignancy. The objective of this project is to assess the impact of SNF2L loss on PCa progression. We hypothesized that SNF2L knockout (KO) will inhibit the proliferation of androgen-sensitive and castration-resistant PCa cells and targeting SNF2L or SMARCA-1 gene may be beneficial for controlling cancer progression. We have generated SNF2L KO PCa cells with CRISPR-Cas9 technology and inhibited SMARCA-1 gene via transient transfection application. Our results showed that SNF2L loss resulted in a reduced proliferation and altered morphology of PCa cells. SNF2L KO destabilizes the NURF complex and impairs chromatin remodeling and histone modifications for cell growth and survival. Thereby, targeting SNF2L may serve as a novel therapeutic regime in PCa control. Citation Format: LaKendria K. Brown, Guoliang Li, Thanigaivelan Kanagasabai, Zhenbang Chen. The oncogenic role of epigenetic factor, SNF2L in PCa [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 2962.