Research Papers:

Androgen receptor transcriptionally regulates semaphorin 3C in a GATA2-dependent manner

Kevin J Tam _, Kush Dalal, Michael Hsing, Chi Wing Cheng, Shahram Khosravi, Parvin Yenki, Charan Tse, James W Peacock, Aishwariya Sharma, Yan Ting Chiang, Yuzhuo Wang, Artem Cherkasov, Paul S Rennie, Martin E Gleave and Christopher J Ong

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Oncotarget. 2017; 8:9617-9633. https://doi.org/10.18632/oncotarget.14168

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Kevin J. Tam1,2, Kush Dalal1, Michael Hsing1, Chi Wing Cheng1, Shahram Khosravi1, Parvin Yenki1,2, Charan Tse1, James W. Peacock1,2, Aishwariya Sharma1, Yan Ting Chiang1,3, Yuzhuo Wang1,3,4, Artem Cherkasov1,4, Paul S. Rennie1,4, Martin E. Gleave1,4, Christopher J. Ong1,2

1Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

2Department of Surgery, University of British Columbia, Vancouver, BC, Canada

3Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada

4Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

Correspondence to:

Christopher J. Ong, email: [email protected]

Keywords: SEMA3C, androgen receptor, GATA2, FOXA1, POU2F1

Received: September 12, 2016     Accepted: December 12, 2016     Published: December 25, 2016


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.

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