ECE2024 Poster Presentations Endocrine-Related Cancer (40 abstracts)
SRSF6 modulates histone-chaperone HIRA splicing to orchestrate androgen and E2F signalling in prostate cancer
Antonio J Montero-Hidalgo 1,2,3,4 , Juan Manuel Jiménez Vacas 1,2,3,4,5 , Enrique Gómez-Gómez 1,3,6 , Ricardo Blázquez-Encinas 1,2,3,4 , Rafael Sánchez-Sánchez 1,3,7 , Antonio Jesús Martínez-Fuentes 1,2,3,4 , Eduardo Eyras 8,9 , Justo P Castaño 1,2,3,4 , Adam Sharp 5,10 , David Olmos 11 , Manuel D Gahete 1,2,3,4 & Raul M Luque 1,2,3,4
1Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); 2University of Cordoba, Department of Cell Biology, Physiology and Immunology; 3Reina Sofia University Hospital (HURS); 4CIBER Physiopathology of Obesity and Nutrition (CIBERobn); 5Institute of Cancer Research; 6Reina Sofia University Hospital (HURS), Urology service; 7Reina Sofia University Hospital (HURS), Anatomical Pathology service; 8The John Curtin School of Medical Research; 9EMBL Australia Partner Laboratory Network at the Australian National University; 10Royal Marsden NHS Foundation Trust; 11Hospital Universitario 12 de Octubre, Department of Medical Oncology
Prostate cancer (PCa) is one of the most common endocrine-related cancers (ERCs) among men worldwide. The aggressiveness of this tumor pathology is highly influenced by different endocrine-related factors, highlighting the crucial role of androgens. Therefore, the main therapeutic approach for PCa patients is based on the pharmacological blockade of androgen-signaling. However, some patients become unresponsive and develop a highly lethal castration-resistant disease, pointing out the urgent need for effective therapeutic strategies. In this regard, the splicing process dysregulation has been considered as a cancer hallmark, but the role of certain splicing-factors remains unknown in different ERCs. Therefore, we aimed to characterize the levels and functional role of SRSF6 in PCa. To that end, we analyzed the SRSF6 levels (copy-number/mRNA/protein) across eight well-characterized PCa cohorts and the Hi-Myc transgenic model. Furthermore, we evaluated the functional response of different normal-like (RWPE-1) and PCa-derived (LNCaP/22Rv1/DU145/PC-3) cell-lines and xenograft models in response to the genetic modulation (overexpression/silencing) of SRSF6. Finally, we performed RNA-Seq together with different bioinformatic analyses to explore the molecular mechanisms underlying the functional effects upon SRSF6 modulation in PCa cells. We found that SRSF6 was upregulated in human and mouse PCa tissues, and its levels were associated with relevant clinical parameters of PCa aggressiveness (e.g. Gleason-score, presence of metastasis at diagnosis, etc.). Additionally, the SRSF6 overexpression increased, while its silencing decreased different functional parameters of tumor aggressiveness <i>in vitro</i>(i.e., proliferation, migration, colonies and tumorsphere formation) and in vivo (i.e., tumor growth, mitosis). Mechanistically, we demonstrated that SRSF6 regulates the splicing pattern of the histone-chaperone HIRA, consequently affecting the activity of the H3.3 histone variant in PCa cells [being also corroborated in breast cancer (BCa) cells] and disrupting pivotal oncogenic pathways [androgen-signaling and E2 Promoter Binding Factor (E2F) activity] in PCa cells. Altogether, our results unveiled new conceptual and functional avenues in PCa, with potential therapeutic implications, by demonstrating that SRSF6 is overexpressed and associated with the aggressiveness of PCa by regulating, among other key oncogenic pathways, AR- and E2F-activity, through the modulation of HIRA splicing. This critical mechanism, also observed in BCa, suggests that SRSF6 is a key player not only in PCa, but also in other ERCs. Therefore, these findings present a unique opportunity for further therapeutic research and clinical exploration of targeting SRSF6 in PCa/advanced-stage PCa, BCa, and, potentially, further ERC types.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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