TY - JOUR
T1 - SRSF6 modulates histone-chaperone HIRA splicing to orchestrate AR and E2F activity in prostate cancer
AU - Montero-Hidalgo, Antonio J.
AU - Jiménez-Vacas, Juan M.
AU - Gómez-Gómez, Enrique
AU - Porcel-Pastrana, Francisco
AU - Sáez-Martínez, Prudencio
AU - Pérez-Gómez, Jesús M.
AU - Fuentes-Fayos, Antonio C.
AU - Blázquez-Encinas, Ricardo
AU - Sánchez-Sánchez, Rafael
AU - González-Serrano, Teresa
AU - Castro, Elena
AU - López-Soto, Pablo J.
AU - Carrasco-Valiente, Julia
AU - Sarmento-Cabral, André
AU - Martinez-Fuentes, Antonio J.
AU - Eyras, Eduardo
AU - Castaño, Justo P.
AU - Sharp, Adam
AU - Olmos, David
AU - Gahete, Manuel D.
AU - Luque, Raúl M.
N1 - Publisher Copyright:
Copyright © 2024 the Authors, some rights reserved.
PY - 2024/10
Y1 - 2024/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85205527583&partnerID=8YFLogxK
U2 - 10.1126/sciadv.ado8231
DO - 10.1126/sciadv.ado8231
M3 - Article
C2 - 39356765
AN - SCOPUS:85205527583
SN - 2375-2548
VL - 10
JO - Science advances
JF - Science advances
IS - 40
M1 - eado8231
ER -