Splicing factor PRPF6 upregulates oncogenic androgen receptor signaling pathway in hepatocellular carcinoma

Abstract

Androgen receptor (AR) signaling is considered to be crucial for the pathogenesis of hepatocellular carcinoma (HCC) with obvious sexual dimorphism. Pre‐mRNA processing factor 6 (PRPF6) was identified as a coactivator of AR. However, what is the molecular mechanism underlying the modulation function of PRPF6 on AR‐mediated transcriptional activity in HCC needs to be further clarified. In this study, we analyzed the data from TCGA to show that PRPF6 is highly expressed in HCC. The highly expression of PRPF6 is positively correlated with the poor prognosis. Our data have demonstrated that PRPF6 interacts with AR/AR splice variants (AR‐Vs) and up‐regulates AR/AR splice variant 7 (AR‐V7)‐mediated transcriptional activity even without DHT treatment. We observed that AR is obviously induced by androgen treatment and is mainly expressed in the nucleus in HCC‐derived cell lines. Moreover, overexpression of PRPF6 enhances AR expression accompanied with the increase of AR‐Vs expression. We provided the evidence that PRPF6 participates in up‐regulating AR itself transcription. PRPF6 facilitates the recruitment of AR to androgen responsive elements (AREs) region of AR gene. Finally, PRPF6 depletion inhibits the cell proliferation in HCC cells and mice xenograft. Taken together, our results suggest that PRPF6 as a splicing factor enhances AR itself transcription, thereby co‐activating oncogenic AR/AR‐Vs actions in HCC.