The splicing factor SRSF6 regulates AR activity and represents a potential therapeutic target in prostate cancer

Abstract

Abstract Background Prostate cancer (PCa) is the fifth leading cause of cancer-related death worldwide. Finding novel therapeutic strategies to tackle PCa, especially its most advanced phenotype, named castration-resistant PCa (CRPC), is urgently needed. In this sense, although the dysregulation of the splicing process has emerged as a distinctive feature of advanced PCa, the potential role that splicing regulators may play in advanced PCa remains understudied. In this project, we aimed to explore the levels, pathophysiological role, and associated molecular landscape of the splicing factor SRSF6 in PCa.Methods SRSF6 alterations (CNA/mRNA/protein) were analyzed in eight well-characterized cohorts of PCa patients and in the Hi-MYC transgenic model. The effect of SRSF6 overexpression and silencing was tested in vitro (cell proliferation, migration, colony and tumorspheres formation), and in vivo (xenograft tumors). RNA-Seq was performed in PCa cells to analyze gene expression and splicing pattern changes in response to SRSF6 silencing.Results Our results showed that SRSF6 levels (mRNA/protein) were upregulated in PCa vs. non-tumor prostate samples, linked to clinical parameters of tumor aggressiveness (e.g., Gleason score, T-stage, perineural infiltration, metastasis at diagnosis), and associated with poor prognosis (i.e., shorter progression-free survival time) in PCa patients. Moreover, SRSF6 overexpression increased, while its silencing decreased, relevant functional parameters of aggressiveness in vitro and tumor growth in vivo. Mechanistically, SRSF6 modulation resulted in the dysregulation of key oncogenic pathways, especially AR-activity through transcriptional regulation of APPBP2 and TOP2BConclusions SRSF6 could represent a new therapeutic target to inhibit persistent AR-signaling in advanced PCa.