An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression

Jindan Yu, Jianjun Yu, Ram Shankar Mani, Qi Cao, Chad J. Brenner, Xuhong Cao, Xiaoju Wang, Longtao Wu, James Li, Ming Hu, Yusong Gong, Hong Cheng, Bharathi Laxman, Adaikkalam Vellaichamy, Sunita Shankar, Yong Li, Saravana M. Dhanasekaran, Roger Morey, Terrence Barrette, Robert J. LonigroScott A. Tomlins, Sooryanarayana Varambally, Zhaohui S. Qin, Arul M. Chinnaiyan*

*Corresponding author for this work

Research output: Contribution to journalArticle

516 Scopus citations

Abstract

Chromosomal rearrangements fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG occur in approximately 50% of prostate cancers, but how the fusion products regulate prostate cancer remains unclear. Using chromatin immunoprecipitation coupled with massively parallel sequencing, we found that ERG disrupts androgen receptor (AR) signaling by inhibiting AR expression, binding to and inhibiting AR activity at gene-specific loci, and inducing repressive epigenetic programs via direct activation of the H3K27 methyltransferase EZH2, a Polycomb group protein. These findings provide a working model in which TMPRSS2-ERG plays a critical role in cancer progression by disrupting lineage-specific differentiation of the prostate and potentiating the EZH2-mediated dedifferentiation program.

Original languageEnglish (US)
Pages (from-to)443-454
Number of pages12
JournalCancer Cell
Volume17
Issue number5
DOIs
Publication statusPublished - May 18 2010

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Keywords

  • CELLCYCLE
  • DNA
  • SIGNALING

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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