title: Androgen receptor transcriptionally regulates semaphorin 3C in a GATA2-dependent manner.
abstract: The androgen receptor (AR) is a member of the nuclear receptor superfamily of transcription factors and is central to prostate cancer (PCa) progression. Ligand-activated AR engages androgen response elements (AREs) at androgen-responsive genes to drive the expression of gene batteries involved in cell proliferation and cell fate. Understanding the transcriptional targets of the AR has become critical in apprehending the mechanisms driving treatment-resistant stages of PCa. Although AR transcription regulation has been extensively studied, the signaling networks downstream of AR are incompletely described. Semaphorin 3C (SEMA3C) is a secreted signaling protein with roles in nervous system and cardiac development but can also drive cellular growth and invasive characteristics in multiple cancers including PCa. Despite numerous findings that implicate SEMA3C in cancer progression, regulatory mechanisms governing its expression remain largely unknown. Here we identify and characterize an androgen response element within the SEMA3C locus. Using the AR-positive LNCaP PCa cell line, we show that SEMA3C expression is driven by AR through this element and that AR-mediated expression of SEMA3C is dependent on the transcription factor GATA2. SEMA3C has been shown to promote cellular growth in certain cell types so implicit to our findings is the discovery of direct regulation of a growth factor by AR. We also show that FOXA1 is a negative regulator of SEMA3C. These findings identify SEMA3C as a novel target of AR, GATA2, and FOXA1 and expand our understanding of semaphorin signaling and cancer biology.
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.|Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tam
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Kush
authors.initials: K
authors.lastname: Dalal
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsing
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Chi Wing
authors.initials: CW
authors.lastname: Cheng
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Shahram
authors.initials: S
authors.lastname: Khosravi
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.|Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Parvin
authors.initials: P
authors.lastname: Yenki
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Charan
authors.initials: C
authors.lastname: Tse
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.|Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: James W
authors.initials: JW
authors.lastname: Peacock
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Aishwariya
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.|Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Yan Ting
authors.initials: YT
authors.lastname: Chiang
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.|Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Artem
authors.initials: A
authors.lastname: Cherkasov
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.|Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D045165:Testosterone Congeners / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; C496499:FOXA1 protein, human; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D011944:Receptors, Androgen; C543908:Sema3C protein, human; D039961:Semaphorins; D045165:Testosterone Congeners
keywords: FOXA1; GATA2; POU2F1; SEMA3C; androgen receptor