Src promotes castration-recurrent prostate cancer through androgen receptor-dependent canonical and non-canonical transcriptional signatures
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Indranil Chattopadhyay1, Jianmin Wang2, Maochun Qin2, Lingqiu Gao3, Renae Holtz3, Robert L. Vessella4, Robert W. Leach5, Irwin H. Gelman3
1Department of Life Sciences, School of Basic and Applied Science, Central University of Tamil Nadu, Thiruvarur, Tamil Nadu, India
2Department of Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
3Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA
4Department of Urology, University of Washington, Seattle, WA, USA
5Lewis-Sigler Institute for Integrative Genomics, Princeton, NJ, USA
Irwin H. Gelman, email: Irwin.firstname.lastname@example.org
Keywords: Src, androgen receptor, castration-recurrent prostate cancer, transcriptome, cistrome
Received: April 03, 2016 Accepted: December 05, 2016 Published: December 31, 2016
Progression of prostate cancer (PC) to castration-recurrent growth (CRPC) remains dependent on sustained expression and transcriptional activity of the androgen receptor (AR). A major mechanism contributing to CRPC progression is through the direct phosphorylation and activation of AR by Src-family (SFK) and ACK1 tyrosine kinases. However, the AR-dependent transcriptional networks activated by Src during CRPC progression have not been elucidated. Here, we show that activated Src (Src527F) induces androgen-independent growth in human LNCaP cells, concomitant with its ability to induce proliferation/survival genes normally induced by dihydrotestosterone (DHT) in androgen-dependent LNCaP and VCaP cells. Src induces additional gene signatures unique to CRPC cell lines, LNCaP-C4-2 and CWR22Rv1, and to CRPC LuCaP35.1 xenografts. By comparing the Src-induced AR-cistrome and/or transcriptome in LNCaP to those in CRPC and LuCaP35.1 tumors, we identified an 11-gene Src-regulated CRPC signature consisting of AR-dependent, AR binding site (ARBS)-associated genes whose expression is altered by DHT in LNCaP[Src527F] but not in LNCaP cells. The differential expression of a subset (DPP4, BCAT1, CNTNAP4, CDH3) correlates with earlier PC metastasis onset and poorer survival, with the expression of BCAT1 required for Src-induced androgen-independent proliferation. Lastly, Src enhances AR binding to non-canonical ARBS enriched for FOXO1, TOP2B and ZNF217 binding motifs; cooperative AR/TOP2B binding to a non-canonical ARBS was both Src- and DHT-sensitive and correlated with increased levels of Src-induced phosphotyrosyl-TOP2B. These data suggest that CRPC progression is facilitated via Src-induced sensitization of AR to intracrine androgen levels, resulting in the engagement of canonical and non-canonical ARBS-dependent gene signatures.
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