THU550 The Splicing Factor SRSF6 Regulates Androgen Receptor Activity And Represents A Potential Therapeutic Target In Prostate Cancer

Disclosure: R.M. Luque: None. A.J. Montero-Hidalgo: None. E. Gomez-Gomez: None. D. Olmos: None. M.D. Gahete: None. J.M. Jimenez-Vacas: None. 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 [i.e., castration-resistant prostate cancer (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 this disease remain poorly understood. In this study, we aimed to analyse the levels, pathophysiological role and associated molecular landscape of the splicing factor SRSF6 in PCa. Methods: SRSF6 levels (mRNA, protein and CNA) were interrogated in seven well-characterized cohorts of PCa patients and in the Hi-MYC transgenic model. The effect of SRSF6 overexpression and silencing was tested in vitro (proliferation, migration, colony- and tumorspheres-formation) and in vivo (tumor growth of xenograft tumours). RNAseq was performed in 22Rv1 cells to analyse splicing and gene expression changes in response to SRSF6 silencing. Findings: Our results showed that SRSF6 levels (mRNA/protein) are upregulated in PCa vs non-tumour prostate samples, linked to clinical parameters of tumour-aggressiveness (e.g., Gleason score, T-stage, perineural infiltration, metastasis at diagnosis), and associated with poor prognosis (i.e., shorter disease-free survival time) in PCa patients. Moreover, SRSF6-overexpression increased, while its silencing decreased, functional parameters of aggressiveness in vitro and tumour growth in vivo. Mechanistically, SRSF6 modulation resulted in dysregulation of Androgen-Receptor (AR) activity through transcriptional control of APPBP2 and TOP2B. Discussion: SRSF6 could represent a new therapeutic target to inhibit persistent AR-signalling in advanced PCa. Funding: Spanish Ministry of Science, Innovation, and Universities (PID2019-105564RB-I00, FPU18/02485), Health Institute Carlos III (DTS20-00050), and CIBERobn. Presentation: Thursday, June 15, 2023