Androgen Receptor Regulates a Distinct Transcription Program in Androgen-Independent Prostate Cancer

Qianben Wang, Wei Li, Yong Zhang, Xin Yuan, Kexin Xu, Jindan Yu, Zhong Chen, Rameen Beroukhim, Hongyun Wang, Mathieu Lupien, Tao Wu, Meredith M. Regan, Clifford A. Meyer, Jason S. Carroll, Arjun Kumar Manrai, Olli A. Jänne, Steven P. Balk, Rohit Mehra, Bo Han, Arul M. ChinnaiyanMark A. Rubin, Lawrence True, Michelangelo Fiorentino, Christopher Fiore, Massimo Loda, Philip W. Kantoff, X. Shirley Liu, Myles Brown

Research output: Contribution to journalArticlepeer-review

607 Scopus citations

Abstract

The evolution of prostate cancer from an androgen-dependent state to one that is androgen-independent marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in androgen-independent cancers is poorly understood. We have defined the direct AR-dependent target genes in both androgen-dependent and -independent cancer cells by generating AR-dependent gene expression profiles and AR cistromes. In contrast to what is found in androgen-dependent cells, AR selectively upregulates M-phase cell-cycle genes in androgen-independent cells, including UBE2C, a gene that inactivates the M-phase checkpoint. We find that epigenetic marks at the UBE2C enhancer, notably histone H3K4 methylation and FoxA1 transcription factor binding, are present in androgen-independent cells and direct AR-enhancer binding and UBE2C activation. Thus, the role of AR in androgen-independent cancer cells is not to direct the androgen-dependent gene expression program without androgen, but rather to execute a distinct program resulting in androgen-independent growth.

Original languageEnglish (US)
Pages (from-to)245-256
Number of pages12
JournalCell
Volume138
Issue number2
DOIs
StatePublished - Jul 23 2009

Keywords

  • HUMDISEASE

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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