Cooperation between Polycomb and androgen receptor during oncogenic transformation

• Type of Material: Article
• Authors: Jonathan C. Zhao, Northwestern University; Jianjun Yu, Northwestern University; Christine Runkle, Northwestern University; Longtao Wu, Northwestern University; Ming Hu, Harvard University; Dayong Wu, Ohio State University; Jun S. Liu, Harvard University; Qianben Wang, Ohio State University; Zhaohui Qin, Emory University; Jindan Yu, Northwestern University
• Language: English
• Date: 2012-02-01
• Publisher: Cold Spring Harbor Laboratory Press
• Publication Version: Final Published Version
• Copyright Statement: © 2012 by Cold Spring Harbor Laboratory Press.
• Final Published Version (URL): http://dx.doi.org/10.1101/gr.131508.111
• Title of Journal or Parent Work: Genome Research
• ISSN: 1088-9051
• Volume: 22
• Issue: 2
• Start Page: 322
• End Page: 331
• Grant/Funding Information: This work was supported by the NIH P50CA69568 Career Development Award (to J.Y.), U54CA143869 pilot project (to J.Y.), R00CA129565 (to J.Y.), R01CA151979 (to Q.W.), and R01HG005119 (to Z.Q.), the U.S. Department of Defense PC080665 (to J.Y.), and the American Cancer Society Research Scholar Award RSG-12-085-01 (to J.Y.).
• Keywords: PROGRAM; TARGET; CADHERIN; BIOCHEMISTRY & MOLECULAR BIOLOGY; CELLS; EXPRESSION; TRANSCRIPTION; REPRESSION; Genetics & Heredity; Life Sciences & Biomedicine; BIOTECHNOLOGY & APPLIED MICROBIOLOGY; INHIBITION; Science & Technology; GENETICS & HEREDITY; PROSTATE-CANCER PROGRESSION; NETWORK; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology
• Research Categories: Health Sciences, Oncology; Biology, Cell

Abstract

Androgen receptor (AR) is a hormone-activated transcription factor that plays important roles in prostate development and function, as well as malignant transformation. The downstream pathways of AR, however, are incompletely understood. AR has been primarily known as a transcriptional activator inducing prostate-specific gene expression. Through integrative analysis of genome-wide AR occupancy and androgen-regulated gene expression, here we report AR as a globally acting transcriptional repressor. This repression is mediated by androgen-responsive elements (ARE) and dictated by Polycomb group protein EZH2 and repressive chromatin remodeling. In embryonic stem cells, AR-repressed genes are occupied by EZH2 and harbor bivalent H3K4me3 and H3K27me3 modifications that are characteristic of differentiation regulators, the silencing of which maintains the undifferentiated state. Concordantly, these genes are silenced in castration-resistant prostate cancer rendering a stem cell-like lack of differentiation and tumor progression. Collectively, our data reveal an unexpected ro le of AR as a transcriptional repressor inhibiting non-prostatic differentiation and, upon excessive signaling, resulting in cancerous dedifferentiation.