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Src promotes castration-recurrent prostate cancer through androgen receptor-dependent canonical and non-canonical transcriptional signatures

2016; Impact Journals LLC; Volume: 8; Issue: 6 Linguagem: Inglês

10.18632/oncotarget.14401

1949-2553

Indranil Chattopadhyay, Jianmin Wang, Maochun Qin, Lingqiu Gao, Renae Holtz, Robert L. Vessella, Robert Leach, Irwin H. Gelman,

Cancer, Lipids, and Metabolism

// Indranil Chattopadhyay 1 , Jianmin Wang 2 , Maochun Qin 2 , Lingqiu Gao 3 , Renae Holtz 3 , Robert L. Vessella 4 , Robert W. Leach 5 , Irwin H. Gelman 3 1 Department of Life Sciences, School of Basic and Applied Science, Central University of Tamil Nadu, Thiruvarur, Tamil Nadu, India 2 Department of Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA 3 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA 4 Department of Urology, University of Washington, Seattle, WA, USA 5 Lewis-Sigler Institute for Integrative Genomics, Princeton, NJ, USA Correspondence to: Irwin H. Gelman, email: Irwin.gelman@roswellpark.org Keywords: Src, androgen receptor, castration-recurrent prostate cancer, transcriptome, cistrome Received: April 03, 2016 Accepted: December 05, 2016 Published: December 31, 2016 ABSTRACT 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.