SRSF6 modulates histone-chaperone HIRA splicing to orchestrate AR and E2F activity in prostate cancer

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dc.contributor.authorMontero-Hidalgo, Antonio J.en
dc.contributor.authorJiménez-Vacas, Juan M.en
dc.contributor.authorGómez-Gómez, Enriqueen
dc.contributor.authorPorcel-Pastrana, Franciscoen
dc.contributor.authorSáez-Martínez, Prudencioen
dc.contributor.authorPérez-Gómez, Jesús M.en
dc.contributor.authorFuentes-Fayos, Antonio C.en
dc.contributor.authorBlázquez-Encinas, Ricardoen
dc.contributor.authorSánchez-Sánchez, Rafaelen
dc.contributor.authorGonzález-Serrano, Teresaen
dc.contributor.authorCastro, Elenaen
dc.contributor.authorLópez-Soto, Pablo J.en
dc.contributor.authorCarrasco-Valiente, Juliaen
dc.contributor.authorSarmento-Cabral, Andréen
dc.contributor.authorMartinez-Fuentes, Antonio J.en
dc.contributor.authorEyras, Eduardoen
dc.contributor.authorCastaño, Justo P.en
dc.contributor.authorSharp, Adamen
dc.contributor.authorOlmos, Daviden
dc.contributor.authorGahete, Manuel D.en
dc.contributor.authorLuque, Raúl M.en
dc.date.accessioned2025-05-23T07:21:19Z
dc.date.available2025-05-23T07:21:19Z
dc.date.issued2024en
dc.description.abstractDespite 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.en
dc.description.sponsorshipWe deeply thank all the patients and the patients\u2019 families for donating the samples and clinical data for research purposes. Special thanks to the staff of Biobank of the iMiBic and the experimental animal service (SAe) of the UcO/iMiBic. Funding: this work was supported by the Spanish Ministry of Science, innovation, and Universities, grants Pid2022-1381850B-i00 (R.M.l.), Pid2019-105564RB-i00 (R.M.l.), FPU16/05059 (A.c.F.-F), FPU17/00263 (P.S.-M.), FPU18/02485 (A.J.M.-H.), FPU18/06009 (J.M.P.-G.), FPU18/02275 (R.B.-e.), and PRe2020-094225 (F.P.-P.); instituto de Salud carlos iii, co-funded by european Union (eRdF/ eSF, \u201Cinvesting in your future\u201D grant dtS20/00050 (R.M.l.); Junta de Andalucia BiO-0139 (R.M.l.); Junta de Andalucia grant Pi-0094-2020 (A.S.-c.); Prostate cancer UK travelling Prize Fellowship (J.M.J.-v.); Wellcome trust clinical Research career development Fellowship (A.S.); and ciBeRobn (ciBeR is an initiative of instituto de Salud carlos iii, Ministerio de Sanidad, Servicios Sociales e igualdad, Spain) Acknowledgments: We deeply thank all the patients and the patients\u2019families for donating the samples and clinical data for research purposes. Special thanks to the staff of Biobank of the iMiBic and the experimental animal service (SAe) of the UcO/iMiBic. Funding: this work was supported by the Spanish Ministry of Science, innovation, and Universities, grants Pid2022-1381850B-i00 (R.M.l.), Pid2019-105564RB-i00 (R.M.l.), FPU16/05059 (A.c.F.-F), FPU17/00263 (P.S.-M.), FPU18/02485 (A.J.M.-H.), FPU18/06009 (J.M.P.-G.), FPU18/02275 (R.B.-e.), and PRe2020-094225 (F.P.-P.); instituto de Salud carlos iii, co-funded by european Union (eRdF/ eSF, \u201Cinvesting in your future\u201Dgrant dtS20/00050 (R.M.l.); Junta de Andalucia BiO-0139 (R.M.l.); Junta de Andalucia grant Pi-0094-2020 (A.S.-c.); Prostate cancer UK travelling Prize Fellowship (J.M.J.-v.); Wellcome trust clinical Research career development Fellowship (A.S.); and ciBeRobn (ciBeR is an initiative of instituto de Salud carlos iii, Ministerio de Sanidad, Servicios Sociales e igualdad, Spain). Author contributions: conceptualization: A.J.M.-H., J.M.J.-v., P.S.-M., A.c.F.-F., J.c.-v., A.J.M.-F., J.P.c., M.d.-G., and R.M.l. data curation: A.J.M.-H., J.M.J.-v., A.J.M.-F., and R.M.l. Formal analysis: A.J.M.-H., J.M.J.-v., P.S.-M., J.M.P.-G., R.B.-e., A.S.-c., A.J.M.-F., d.O., and R.M.l. Funding acquisition: J.P.c. and R.M.l. investigation: A.J.M.-H., J.M.J.-v., e.G.-G., F.P.-P., P.S.-M., J.M.P.-G., A.c.F.-F., R.B.-e., e.c., P.J.l.-S., A.S.-c., A.J.M.-F., and R.M.l. Methodology: A.J.M.-H., J.M.J.-v., P.S.-M., A.c.F.-F., J.c.-v., A.J.M.-F., J.P.c., d.O., M.d.-G., and R.M.l. Project administration: J.M.J.-v., A.J.M.-F., d.O., M.d.-G., and R.M.l. Resources: A.J.M.-H., F.P.-P., J.M.P.-G., R.S.-S., t.G.-S., e.c., J.c.-v., A.J.M.-F., J.P.c., d.O., and R.M.l. Software: J.M.J.-v., R.B.e., J.c.-v., and A.J.M.-F. Supervision: J.M.J.-v., A.J.M.-F., A.S., M.d.-G., and R.M.l. validation: A.J.M.-H., J.M.J.-v., P.S.-M., e.c., J.c.-v., A.J.M.-F., d.O., and R.M.l. visualization: A.J.M.-H., J.M.J.-v., e.G.-G., R.B.-e., e.c., A.J.M.-F., and R.M.l. Writing\u2014original draft: A.J.M.-H., J.M.J.-v., A.J.M.-F., e.e., and R.M.l. Writing\u2014review and editing: A.J.M.-H., J.M.J.-v., P.S.-M., A.c.F.-F., R.B.-e., e.c., A.J.M.-F., e.e., J.P.c., A.S., and R.M.l. Competing interests: A.S. is an employee of the icR, which has a commercial interest in abiraterone, poly(adenosine 5\u2032-diphosphate\u2013ribose) polymerase inhibition in dnA repair defective cancers, and phosphatidylinositol 3-kinase/Akt pathway inhibitors (no personal income). A.S. has received travel support from Sanofi, Roche-Genentech, and nurix and speaker honoraria from Astellas Pharma and Merck Sharp & dohme. He has served as an advisor to de Shaw Research, cHARM therapeutics, ellipses Pharma, and droia ventures. A.S. has been the ci/Pi of industry-sponsored clinical trials. the other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.en
dc.description.statusPeer-revieweden
dc.identifier.otherPubMed:39356765en
dc.identifier.otherORCID:/0000-0003-0793-6218/work/184100341en
dc.identifier.scopus85205527583en
dc.identifier.urihttp://www.scopus.com/inward/record.url?scp=85205527583&partnerID=8YFLogxKen
dc.identifier.urihttps://hdl.handle.net/1885/733751681
dc.language.isoenen
dc.rightsPublisher Copyright: Copyright © 2024 the Authors, some rights reserved.en
dc.sourceScience advancesen
dc.titleSRSF6 modulates histone-chaperone HIRA splicing to orchestrate AR and E2F activity in prostate canceren
dc.typeJournal articleen
dspace.entity.typePublicationen
local.contributor.affiliationMontero-Hidalgo, Antonio J.; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationJiménez-Vacas, Juan M.; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationGómez-Gómez, Enrique; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationPorcel-Pastrana, Francisco; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationSáez-Martínez, Prudencio; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationPérez-Gómez, Jesús M.; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationFuentes-Fayos, Antonio C.; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationBlázquez-Encinas, Ricardo; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationSánchez-Sánchez, Rafael; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationGonzález-Serrano, Teresa; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationCastro, Elena; Biomedical Research institute of Málagaen
local.contributor.affiliationLópez-Soto, Pablo J.; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationCarrasco-Valiente, Julia; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationSarmento-Cabral, André; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationMartinez-Fuentes, Antonio J.; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationEyras, Eduardo; Genome Sciences and Cancer Division, John Curtin School of Medical Research, ANU College of Science and Medicine, The Australian National Universityen
local.contributor.affiliationCastaño, Justo P.; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationSharp, Adam; Institute of Cancer Researchen
local.contributor.affiliationOlmos, David; Hospital Universitario 12 de Octubreen
local.contributor.affiliationGahete, Manuel D.; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.contributor.affiliationLuque, Raúl M.; Maimonides Biomedical Research Institute of Córdoba (IMIBIC)en
local.identifier.citationvolume10en
local.identifier.doi10.1126/sciadv.ado8231en
local.identifier.pure53413870-ea32-4d9d-b17a-182fc6ef8484en
local.identifier.urlhttps://www.scopus.com/pages/publications/85205527583en
local.type.statusPublisheden

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