title: Src promotes castration-recurrent prostate cancer through androgen receptor-dependent canonical and non-canonical transcriptional signatures.
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.
authors.affiliation: Department of Life Sciences, School of Basic and Applied Science, Central University of Tamil Nadu, Thiruvarur, Tamil Nadu, India.
authors.forename: Indranil
authors.initials: I
authors.lastname: Chattopadhyay
authors.affiliation: Department of Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Maochun
authors.initials: M
authors.lastname: Qin
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Lingqiu
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Renae
authors.initials: R
authors.lastname: Holtz
authors.affiliation: Department of Urology, University of Washington, Seattle, WA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton, NJ, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Leach
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Irwin H
authors.initials: IH
authors.lastname: Gelman
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D013196:Dihydrotestosterone / Q000494:pharmacology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D059467:Transcriptome; D014162:Transfection; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D019061:src-Family Kinases
keywords: Src; androgen receptor; castration-recurrent prostate cancer; cistrome; transcriptome