Endocrine Abstracts

Prostate cancer (PCa) represents the most diagnosed tumour pathology in developed countries among men population. The main pharmacological approach to treat this pathology is based on the blockade of the androgen receptor signalling pathway, commonly known as androgen-deprivation therapy. However, some of the patients does no longer respond to this therapy, therefore developing castration-resistant prostate cancer (CRPC), the most aggressive phenotype of this pathology, which remains lethal nowadays. Therefore, new molecular targets with potential to identify more effective therapeutic strategies are extremely needed. In this sense, alteration of RNA-splicing process has raised as a new hallmark of cancer. Herein, we studied the presence and pathophysiological role of SRSF6, a splicing factor that has been reported to have an oncogenic potential in other tumor-types (e.g., ovarian, lung and colon). To that aim, SRSF6 levels were interrogated by quantitative real-time PCR (mRNA levels) and immunohistochemistry (protein levels), in two well-characterized cohorts: 1) fresh PCa (n=42) and control (n=9) samples, and 2) formalin-fixed, paraffin-embedded PCa (n=84) and non-tumour adjacent tissue (n=84) samples. Additionally, functional and mechanistic assays were performed in different cell models [PCa cells (LNCaP, 22Rv1, DU145, and PC-3) and non-tumour prostate cells (PNT2)] in response to SRSF6 silencing (using a specific siRNA). Moreover, the effect of SRSF6 in vivo silencing was also tested using a xenograft mouse model. Finally, we also analysed in vitro the putative relationship between the expression levels of SRSF6 with the androgen signalling and the resistance to androgen-deprivation therapy. Our results revealed that SRSF6 is upregulated (at mRNA and protein levels) in PCa samples and its levels are directly associated to key clinical and molecular parameters of PCa aggressiveness [e.g., Gleason grade, androgen-receptor (AR) signalling pathway]. Furthermore, the silencing of SRSF6 significantly decreased critical functional aggressiveness parameters in PCa cells (i.e. proliferation and migration rates and tumorsphere formation). Mechanistically, SRSF6 silencing altered the splicing process of AR, by reducing specifically the oncogenic splicing variant AR-V7. Consistently, a preclinical approach showed that the treatment with SRSF6 siRNA reduced the size of 22Rv1-derived tumours, impacting key molecular pathways (e.g., AR signalling). Taken together, our results suggest that SRSF6 impact AR signalling by dysregulating AR-V7 splicing and that its targeting could represent a novel and promising therapeutic strategy for the treatment of advanced PCa.