H3K9 methylation drives resistance to androgen receptor–antagonist therapy in prostate cancer
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ABSTRACT:
PROVIDER: PRJNA835482 | ENA |
REPOSITORIES: ENA
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Project description:The study was performed to identify the role of H3K9 methylation in prostate cancer. This experiment was conducted to determine the genomic localization of H3K9me2 and H3K9me3 in naïve, short-term antiandrogen treated and antiandrogen resistant prostate cancer cells.
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Project description:Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles for the male sex hormone androgen and its receptor (AR) in melanoma, cellular and molecular mechanisms underlying these sex-associated discrepancies are poorly defined. Here, we delineate a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 (FUT4) expression, which drives melanoma invasiveness by interfering with adherens junctions (AJs). Global phosphoproteomic and fucoproteomic profiling, coupled with in vitro and in vivo functional validation, further reveals that AR-induced FUT4 fucosylates L1 cell adhesion molecule (L1CAM), which is required for FUT4-increased metastatic capacity. Tumor microarray and gene expression analyses demonstrate that AR-FUT4-L1CAM-AJs signaling correlates with pathological staging in melanoma patients. By delineating key androgen-triggered signaling that enhances metastatic aggressiveness, our findings help to explain sex-associated clinical outcome disparities and highlight AR/FUT4 and its effectors as potential prognostic biomarkers and therapeutic targets in melanoma.
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Project description:Prostate epithelial cells depend on androgens for survival and function. In early prostate cancer, besides survival, androgens also regulated tumor growth, which is exploited by androgen ablation/ blockade therapies in metastatic disease. The aim of the present study was to characterize the role of the androgen receptor pathway in prostate cancer progression and to identify potential disease markers. Microarray analysis was used to establish the androgen-regulated gene expression profile, upon stimulation with the synthetic androgen R1881 or the antiandrogen hydroxyflutamide, of the androgen-responsive PC346C cell line and its derivative castration-resistant sublines: PC346DCC (vestigial AR levels), PC346Flu1 (AR overexpression) and PC346Flu2 (T877A mutated AR) PC346C, PC346DCC, PC346Flu1 and PC346Flu2 were stimulated with 1 nM R1881, 1uM hydroxyflutamide or vehicle control, following a 4, 8 and 16h time-course. Each condition was performed in dye-swap, using biological duplicates. PC346DCC was only stimulated with R1881, not hydroxyflutamide.
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Project description:We report the androgen receptor recruitment to the chromatin of androgen responsive prostate cancer cell lines, LNCaP-1F5 and VCaP in response to physiological androgen 5a-dihydrotestosterone (DHT) using ChIP-sequencing. We compare the AR recruitment by DHT to that by partial agonist/antagonist cyproterone acetate (CPA), mifepristone (RU486) and bicalutamide (Bica) in LNCaP-1F5 cells. We also report the role of glucocorticoid receptor recruitment in presence of dexamethasone (Dex) in androgen responsive prostate cancer cells. The AR and GR cistrome analysis is subsequently compared with gene expression data and RNA Pol II analysis. The ChIP-seq has been performed using AR, GR, RNA Pol II antibodies.
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