Work

MED1 mediates androgen receptor splice variant induced gene expression in the absence of ligand

Year: 2014

Type: article

Abstract: // Gang Liu 1 , Cynthia Sprenger 1, 2 , Pin-Jou Wu 1 , Shihua Sun 1 , Takuma Uo 1 , Kathleen Haugk 2 , Kathryn Soriano Epilepsia 1 , Stephen Plymate 1, 2 1 Department of Medicine, University of Washington, Seattle 98104, WA, USA 2 Veteran Affairs Puget Sound Health Care System, Seattle 98104, WA, USA Correspondence to: Stephen Plymate, e-mail: [email protected] Keywords: prostate cancer, androgen receptor splice variant, ARv567es, MED1, UBE2C Received: July 01, 2014 Accepted: November 02, 2014 Published: January 28, 2015 ABSTRACT The appearance of constitutively active androgen receptor splice variants (AR-Vs) has been proposed as one of the causes of castration-resistant prostate cancer (CRPC). However, the underlying mechanism of AR-Vs in CRPC transcriptional regulation has not been defined. A distinct transcriptome enriched with cell cycle genes, e.g. UBE2C, has been associated with AR-Vs, which indicates the possibility of an altered transcriptional mechanism when compared to full-length wild-type AR (AR fl ). Importantly, a recent study reported the critical role of p-MED1 in enhancing UBE2C expression through a locus looping pattern, which only occurs in CRPC but not in androgen-dependent prostate cancer (ADPC). To investigate the potential correlation between AR-V and MED1, in the present study we performed protein co-immunoprecipitation, chromatin immunoprecipitation, and cell proliferation assays and found that MED1 is necessary for AR v567es induced UBE2C up-regulation and subsequent prostate cancer cell growth. Furthermore, p-MED1 is bound to AR v567es independent of full-length AR; p-MED1 has higher recruitment to UBE2C promoter and enhancer regions in the presence of AR v567es . Our data indicate that p-MED1 serves as a key mediator in AR v567es induced gene expression and suggests a mechanism by which AR-Vs promote the development and progression of CRPC.

Source: Oncotarget

DOI: 10.18632/oncotarget.2672