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.

Emerging data on androgen receptor splice variants in prostate cancer

“…In the presence of androgen, MED1 has been shown to interact with the LBD of AR-FL and enhance androgen-dependent AR-FL activity (Wang, et al 2002). In androgen-deprived condition, PI3K/AKT phosphorylated MED1 (p-MED1) can enhance both AR-FL- and AR v567es -mediated UBE2C transcription through an enhancer-promoter chromatin-looping mechanism (Chen, et al 2011; Liu, et al 2015b; Wang, et al 2009). However, AR v567es , with the assistance of the pioneer factor FOXA1, has been shown to be more potent than AR-FL to recruit p-MED1 to the promoter and enhancer regions of UBE2C (Liu et al 2015b).…”

“…In androgen-deprived condition, PI3K/AKT phosphorylated MED1 (p-MED1) can enhance both AR-FL- and AR v567es -mediated UBE2C transcription through an enhancer-promoter chromatin-looping mechanism (Chen, et al 2011; Liu, et al 2015b; Wang, et al 2009). However, AR v567es , with the assistance of the pioneer factor FOXA1, has been shown to be more potent than AR-FL to recruit p-MED1 to the promoter and enhancer regions of UBE2C (Liu et al 2015b). This may underlie the preferential regulation of UBE2C by AR-Vs over AR-FL in cells co-expressing AR-FL and AR-Vs (Cao et al 2014; Hu et al 2012).…”

Variation is function: Are single cell differences functionally important?

“…This suggests that variability of RNA expression for particular systems may be more easily manipulated using miRNAs. Tight regulation of abundances can be achieved, again using the cumate operon . Performing time courses by turning the miRNAs on and off within the same cells and quantifying changes in population phenotype and transcriptome variability promises to highlight functional components of cellular transcriptome variability.…”

Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation

“…ARV expression serves as a predictive biomarker for response to enzalutamide or abiraterone acetate (12). ARVs are nuclear, constitutively active, bind to similar androgen response elements (AREs), as that engaged by full length AR (ARfl) (13), and interact with similar coregulators as ARfl (14–16). Thus, ARVs may substitute for ARfl, when the ARfl is effectively blocked by ADT (13).…”