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.
Highlights
Castration-resistant prostate cancer (CRPC) occurs when androgen ablation therapy fails
To investigate whether MED1 is involved in this regulatory activity, MED1 expression was silenced by RNA interference (RNAi) (Fig. S1)
The androgen receptor splices variants (AR-Vs) induce a distinct transcriptome in which www.impactjournals.com/oncotarget overexpression of ubiquitin-conjugating enzyme E2C (UBE2C) and other cell cycle genes predominate, suggesting there might be different, or unique, transcriptional machinery used by androgen receptor (AR) variants compared to full-length AR
Summary
Castration-resistant prostate cancer (CRPC) occurs when androgen ablation therapy fails. Various cytokines and growth factors have been shown to activate AR through direct binding or by cross-talk mechanisms [8, 9]. AR-Vs have been identified by several independent groups in human prostate cancer cell lines, xenografts, metastases, and circulating tumor cells [10,11,12,13,14,15]. Most characteristically, these variants are devoid of the ligand binding domain (LBD) but retain the capability to engage transcriptional machinery and promote the regulation of AR-target genes. The AR3/ V7 and ARv567es transgenic mouse models demonstrated that expression of AR variant in mouse prostate induced www.impactjournals.com/oncotarget high-grade prostatic intraepithelial neoplasia (PIN) [20] and/or invasive prostatic carcinoma [21]
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