Abstract
Standard treatment for metastatic prostate cancer (CaP) prevents ligand-activation of androgen receptor (AR). Despite initial remission, CaP progresses while relying on AR. AR transcriptional output controls CaP behavior and is an alternative therapeutic target, but its molecular regulation is poorly understood. Here, we show that action of activated AR partitions into fractions that are controlled preferentially by different coregulators. In a 452-AR-target gene panel, each of 18 clinically relevant coregulators mediates androgen-responsiveness of 0-57% genes and acts as a coactivator or corepressor in a gene-specific manner. Selectivity in coregulator-dependent AR action is reflected in differential AR binding site composition and involvement with CaP biology and progression. Isolation of a novel transcriptional mechanism in which WDR77 unites the actions of AR and p53, the major genomic drivers of lethal CaP, to control cell cycle progression provides proof-of-principle for treatment via selective interference with AR action by exploiting AR dependence on coregulators.
Highlights
The androgen-activated androgen receptor (AR) is both the major driver of prostate cancer (CaP) progression and the main target for treatment of metastatic CaP
Expression profiles of androgen-regulated genes do not distinguish between direct AR target genes, which are androgenresponsive because of direct AR-Androgen Response Element (ARE) interaction, and indirect AR target genes, which are androgenregulated secondary to the action of a direct AR target gene
We reasoned that integrating information on the genome-wide location of AR binding sites (ARBSs), transcriptional start site (TSS) position, and androgen-responsive gene expression would result in identification of bona fide direct AR target genes
Summary
The androgen-activated androgen receptor (AR) is both the major driver of prostate cancer (CaP) progression and the main target for treatment of metastatic CaP. Cancer Biology eLife digest Prostate cancer is the second leading cause of cancer deaths in men in the Western world. Almost all of these deaths happen when the main treatment for advanced prostate cancers stops working. The treatment, known as androgen deprivation therapy, targets a protein called the androgen receptor. This receptor is activated when it binds to signaling molecules and, once active, it switches on genes that encourage the cancer cells to grow. Androgen deprivation therapy blocks the androgen receptor from interacting with the signaling molecules; this treatment eventually fails because the receptor finds other ways to remain active in prostate cancer
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.