Androgen deprivation–induced NCoA2 promotes metastatic and castration-resistant prostate cancer
Jun Qin, … , Sophia Y. Tsai, Ming-Jer Tsai
Jun Qin, … , Sophia Y. Tsai, Ming-Jer Tsai
Published November 3, 2014; First published October 8, 2014
Citation Information: J Clin Invest. 2014;124(11):5013-5026. https://doi.org/10.1172/JCI76412.
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Research Article Oncology

Androgen deprivation–induced NCoA2 promotes metastatic and castration-resistant prostate cancer

Abstract

A major clinical hurdle for the management of advanced prostate cancer (PCa) in patients is the resistance of tumors to androgen deprivation therapy (ADT) and their subsequent development into castration-resistant prostate cancer (CRPC). While recent studies have identified potential pathways involved in CRPC development, the drivers of CRPC remain largely undefined. Here we determined that nuclear receptor coactivator 2 (NCoA2, also known as SRC-2), which is frequently amplified or overexpressed in patients with metastatic PCa, mediates development of CRPC. In a murine model, overexpression of NCoA2 in the prostate epithelium resulted in neoplasia and, in combination with Pten deletion, promoted the development of metastasis-prone cancer. Moreover, depletion of NCoA2 in PTEN-deficient mice prevented the development of CRPC. In human androgen-sensitive prostate cancer cells, androgen signaling suppressed NCoA2 expression, and NCoA2 overexpression in murine prostate tumors resulted in hyperactivation of PI3K/AKT and MAPK signaling, promoting tumor malignance. Analysis of PCa patient samples revealed a strong correlation among NCoA2-mediated signaling, disease progression, and PCa recurrence. Taken together, our findings indicate that androgen deprivation induces NCoA2, which in turn mediates activation of PI3K signaling and promotes PCa metastasis and CRPC development. Moreover, these results suggest that the inhibition of NCoA2 has potential for PCa therapy.

Authors

Jun Qin, Hui-Ju Lee, San-Pin Wu, Shih-Chieh Lin, Rainer B. Lanz, Chad J. Creighton, Francesco J. DeMayo, Sophia Y. Tsai, Ming-Jer Tsai

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Figure 5

NCoA2 directly regulates key components of PI3K/AKT and MAPK pathways to promote CRPC.

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NCoA2 directly regulates key components of PI3K/AKT and MAPK pathways to...
(A) ChIP-seq results of NCoA2 binding in the Fkbp5, Phlpp1, and Pten locus. Numbers indicate NCoA2 binding sites (top). N indicates a region without NCoA2 binding sites that served as a negative control. ChIP-PCR assays for NCoA2 binding to Fkbp5, Phlpp1, and Pten genes on pooled 7-month-old PTENPC+/– NCoA2PCOE/+ prostate samples using anti-Flag antibody (NCoA2 with Flag tag) or IgG (bottom). Bar graphs show an enrichment of DNA fragments pulled down by anti-Flag antibodies. (B) Left: ChIP-seq result of NCoA2 binding in the Map3k1 and Rac-GEF locus. Right: ChIP-PCR assays for NCoA2 binding to Map3k1 and Rac-GEF genes are as denoted. (C) Relative mRNA levels of denoted genes from PTENPC+/– and PTENPC+/– NCoA2PCOE/+ prostates (n = 6). (D–F) IHC analysis of phospho-AKT (D), FKBP5 (E) and PHLPP1 (F) expression in prostate tumors isolated from PTENPC–/– and PTENPC–/– NCoA2PC–/– mice with or without castration (6 months after castration). Student’s t test was used for all the statistical analysis. Scale bars: 50 μm (D–F). *P < 0.05; **P < 0.01.