SRSF6 modulates histone-chaperone HIRA splicing to orchestrate AR and E2F activity in prostate cancer
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 <i>HIRA</i>, 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.
Authors
- Enrique Gómez‐Gómez (ORCID: https://orcid.org/0000-0002-8753-3306)
- Raul Miguel Luque (ORCID: https://orcid.org/0000-0002-7585-1913)
- Manuel David Gahete (ORCID: https://orcid.org/0000-0002-4578-2179)
- Teresa González Serrano (ORCID: https://orcid.org/0000-0002-8034-0480)
- Francisco Porcel-Pastrana (ORCID: https://orcid.org/0000-0002-1664-2556)
- Antonio C. Fuentes-Fayos (ORCID: https://orcid.org/0000-0003-2069-4823)
- Prudencio Sáez-Martínez (ORCID: https://orcid.org/0000-0001-5909-3553)
- Juan M. Jiménez‐Vacas (ORCID: https://orcid.org/0000-0003-4391-3726)
- Julia Carrasco‐Valiente
- André Sarmento‐Cabral (ORCID: https://orcid.org/0000-0002-1204-0371)
- Justo P. Castaño (ORCID: https://orcid.org/0000-0002-3145-7287)
- Antonio J. Montero‐Hidalgo (ORCID: https://orcid.org/0000-0002-1948-7512)
- Eduardo Eyras (ORCID: https://orcid.org/0000-0003-0793-6218)
- Ricardo Blázquez‐Encinas (ORCID: https://orcid.org/0000-0003-2904-8625)
- Adam Sharp (ORCID: https://orcid.org/0000-0002-3740-1612)
- Antonio J. Martínez‐Fuentes (ORCID: https://orcid.org/0000-0003-0994-1037)
- Jesús M. Pérez‐Gómez (ORCID: https://orcid.org/0000-0003-1785-9797)
- David Olmos (ORCID: https://orcid.org/0000-0002-7003-4826)
- Elena Castro (ORCID: https://orcid.org/0000-0002-3691-6454)
- Pablo Jesús López‐Soto (ORCID: https://orcid.org/0000-0002-1046-6686)
- Rafael Sánchez-Sánchez (ORCID: https://orcid.org/0000-0002-9497-2315)
Institutions
- Australian National University (AU)
- Royal Marsden NHS Foundation Trust (GB)
- Institute of Cancer Research (GB)
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (ES)
- Research Institute Hospital 12 de Octubre (ES)
- Instituto Maimónides de Investigación Biomédica de Córdoba (ES)
- EMBL Australia (AU)
- Hospital Universitario 12 De Octubre (ES)
- Centro de Investigación Biomédica en Red (ES)
- Hospital Universitario Reina Sofía (ES)
- Instituto de Investigación Biomédica de Málaga (ES)
- University of Córdoba (ES)
- Universidad de Málaga (ES)
Publication Details
- Journal
- Science Advances
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1126/sciadv.ado8231
- Citations
- 7
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- Medical Research Council