1. SRSF6 modulates histone-chaperone HIRA splicing to orchestrate AR and E2F activity in prostate cancer.
- Author
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Montero-Hidalgo AJ, Jiménez-Vacas JM, Gómez-Gómez E, Porcel-Pastrana F, Sáez-Martínez P, Pérez-Gómez JM, Fuentes-Fayos AC, Blázquez-Encinas R, Sánchez-Sánchez R, González-Serrano T, Castro E, López-Soto PJ, Carrasco-Valiente J, Sarmento-Cabral A, Martinez-Fuentes AJ, Eyras E, Castaño JP, Sharp A, Olmos D, Gahete MD, and Luque RM
- Subjects
- Humans, Male, Animals, Cell Line, Tumor, Receptors, Androgen metabolism, Receptors, Androgen genetics, Gene Expression Regulation, Neoplastic, Mice, RNA Splicing, Cell Proliferation, Histones metabolism, Cell Cycle Proteins metabolism, Cell Cycle Proteins genetics, Transcription Factors metabolism, Transcription Factors genetics, Phosphoproteins, Serine-Arginine Splicing Factors metabolism, Serine-Arginine Splicing Factors genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Histone Chaperones metabolism, Histone Chaperones genetics
- Abstract
Despite novel therapeutic strategies, advanced-stage prostate cancer (PCa) remains highly lethal, pointing out the urgent need for effective therapeutic strategies. While dysregulation of the splicing process is considered a cancer hallmark, the role of certain splicing factors remains unknown in PCa. This study focuses on characterizing the levels and role of SRSF6 in this disease. Comprehensive analyses of SRSF6 alterations (copy number/mRNA/protein) were conducted across eight well-characterized PCa cohorts and the Hi-MYC transgenic model. SRSF6 was up-regulated in PCa samples, correlating with adverse clinical parameters. Functional assays, both in vitro (cell proliferation, migration, colony, and tumorsphere formation) and in vivo (xenograft tumors), demonstrated the impact of SRSF6 modulation on critical cancer hallmarks. Mechanistically, SRSF6 regulates the splicing pattern of the histone-chaperone HIRA , consequently affecting the activity of H3.3 in PCa and breast cancer cell models and disrupting pivotal oncogenic pathways (AR and E2F) in PCa cells. These findings underscore SRSF6 as a promising therapeutic target for PCa/advanced-stage PCa.
- Published
- 2024
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