title: MED1 mediates androgen receptor splice variant induced gene expression in the absence of ligand.
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 (ARfl). 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 ARv567es induced UBE2C up-regulation and subsequent prostate cancer cell growth. Furthermore, p-MED1 is bound to ARv567es independent of full-length AR; p-MED1 has higher recruitment to UBE2C promoter and enhancer regions in the presence of ARv567es. Our data indicate that p-MED1 serves as a key mediator in ARv567es induced gene expression and suggests a mechanism by which AR-Vs promote the development and progression of CRPC.
authors.affiliation: Department of Medicine, University of Washington, Seattle 98104, WA, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Washington, Seattle 98104, WA, USA. Veteran Affairs Puget Sound Health Care System, Seattle 98104, WA, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sprenger
authors.affiliation: Department of Medicine, University of Washington, Seattle 98104, WA, USA.
authors.forename: Pin-Jou
authors.initials: PJ
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of Washington, Seattle 98104, WA, USA.
authors.forename: Shihua
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Medicine, University of Washington, Seattle 98104, WA, USA.
authors.forename: Takuma
authors.initials: T
authors.lastname: Uo
authors.affiliation: Veteran Affairs Puget Sound Health Care System, Seattle 98104, WA, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Haugk
authors.affiliation: Department of Medicine, University of Washington, Seattle 98104, WA, USA.
authors.forename: Kathryn Soriano
authors.initials: KS
authors.lastname: Epilepsia
authors.affiliation: Department of Medicine, University of Washington, Seattle 98104, WA, USA. Veteran Affairs Puget Sound Health Care System, Seattle 98104, WA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Plymate
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D056913:Mediator Complex Subunit 1 / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics*; D014162:Transfection; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics
chemical_list: C410798:AR protein, human; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes