Androgen Receptor Tumor Suppressor Function Is Mediated by Recruitment of Retinoblastoma Protein.

Although well characterized as a transcriptional activator that drives prostate cancer (PCa) growth, androgen receptor (AR) can function as a transcriptional repressor, and high-level androgens can suppress PCa proliferation. The molecular basis for this repression activity remains to be determined. Genes required for DNA replication are highly enriched among androgen-repressed genes, and AR is recruited to the majority of these genes, where it rapidly represses their transcription. This activity is enhanced in PCa cells expressing high AR levels and is mediated by recruitment of hypophosphorylated retinoblastoma protein (Rb). Significantly, AR also indirectly increases the expression of DNA replication genes through stimulatory effects on other metabolic genes with subsequent CDK activation and Rb hyperphosphorylation. In castration-resistant PCa cells, which are dependent on high-level AR expression, this anti-proliferative repression function might be exploited through treatment with androgen in combination with agents that suppress AR-driven metabolic functions or cell cycle progression.

Cell reports. 2016 Oct 18 [Epub]

Shuai Gao, Yanfei Gao, Housheng Hansen He, Dong Han, Wanting Han, Amy Avery, Jill A Macoska, Xiaming Liu, Sen Chen, Fen Ma, Shaoyong Chen, Steven P Balk, Changmeng Cai

Center for Personalized Cancer Therapy, University of Massachusetts, Boston, Boston, MA 02125, USA; Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA., Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Orthopedics, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China., Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, Toronto, ON M5G1L7, Canada., Center for Personalized Cancer Therapy, University of Massachusetts, Boston, Boston, MA 02125, USA., Department of Urology, Tongji Hospital, Wuhan, Hubei 430030, China., Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA., Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address: ., Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address: ., Center for Personalized Cancer Therapy, University of Massachusetts, Boston, Boston, MA 02125, USA; Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address: .

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