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

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 targe...

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Bibliographic Details
Published in:Cell 2009-07, Vol.138 (2), p.245-256
Main Authors: Wang, Qianben, Li, Wei, Zhang, Yong, Yuan, Xin, Xu, Kexin, Yu, Jindan, Chen, Zhong, Beroukhim, Rameen, Wang, Hongyun, Lupien, Mathieu, Wu, Tao, Regan, Meredith M., Meyer, Clifford A., Carroll, Jason S., Manrai, Arjun Kumar, Jänne, Olli A., Balk, Steven P., Mehra, Rohit, Han, Bo, Chinnaiyan, Arul M., Rubin, Mark A., True, Lawrence, Fiorentino, Michelangelo, Fiore, Christopher, Loda, Massimo, Kantoff, Philip W., Liu, X. Shirley, Brown, Myles
Format: Article
Language:English
Subjects:
Androgens - metabolism
Cell Division
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Hepatocyte Nuclear Factor 3-alpha - metabolism
Histones - metabolism
Humans
HUMDISEASE
Male
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Receptors, Androgen - metabolism
Transcriptional Activation
Ubiquitin-Conjugating Enzymes - metabolism
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Summary: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.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2009.04.056