ECE2023 Poster Presentations Endocrine-related Cancer (62 abstracts)
Therapeutic potential of the splicing factor SRSF6 as a novel regulator of the Androgen Receptor in prostate cancer
Antonio J. Montero-Hidalgo 1,2,3,4 , Enrique Gómez-Gómez 1,3,4,5 , Prudencio Sáez-Martínez 1,2,3,4 , Antonio C. Fuentes-Fayos 1,2,3,4 , Rafael Sánchez-Sánchez 1,3,4,6 , David Olmos 7 , Antonio Jesús Martínez-Fuentes 1,2,3,4 , André Sarmento-Cabral 1,2,3,4 , Manuel D. Gahete 1,2,3,4 , Juan Manuel Jiménez Vacas 1,2,3,4 & Raul M Luque 1,2,3,4
1Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain; 2University of Cordoba, Department of Cell Biology, Physiology and Immunology, Cordoba, Spain; 3Reina Sofia University Hospital (HURS), Cordoba, Spain; 4CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain; 5Reina Sofia University Hospital (HURS), Urology service, Cordoba, Spain; 6Reina Sofia University Hospital (HURS), Anatomical Pathology service, Cordoba, Spain; 7Hospital Universitario 12 de Octubre, Madrid, Spain
Background: Prostate cancer (PCa) is the fifth leading cause of cancer-related death worldwide. The main pharmacological strategy for this pathology is 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 hormonal therapy. Therefore, 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 explored. In this study, we aimed to analyse the levels, pathophysiological role, and associated molecular features of the splicing factor SRSF6 in PCa.
Methods: SRSF6 levels (copy-number, mRNA, and protein) were interrogated in seven well-characterized cohorts of PCa patients and in the Hi-MYC transgenic model. The functional/molecular effects of SRSF6 overexpression and silencing were evaluated in vitro [using different PCa-derived (LNCaP, 22Rv1, DU145, and PC-3) and non-tumour prostate (RWPE-1) cells] and in vivo (tumour growth in xenograft models). RNAseq was performed in 22Rv1 cells to analyse splicing and gene expression alterations in response to SRSF6 silencing.
Results: 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) in PCa patients. Moreover, SRSF6-overexpression increased, while SRSF6-silencing decreased, functional parameters of aggressiveness in vitro (proliferation, migration, colonies- and tumorspheres-formation) and tumour growth in vivo. Mechanistically, SRSF6 modulation resulted into a dysregulation of Androgen-Receptor (AR) activity through transcriptional control of the AR-coregulators APPBP2 and TOP2B.
Discussion: SRSF6 could represent a new therapeutic target to inhibit persistent AR-signalling in advanced PCa.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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