Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes

Jiménez-Vacas, Juan M.; Montero-Hidalgo, Antonio J.; Gómez-Gómez, Enrique; Sáez-Martínez, Prudencio; Fuentes-Fayos, Antonio C.; Closa, Adrià; González-Serrano, Teresa; Martínez-López, Ana; Sánchez-Sánchez, Rafael; López-Casas, Pedro P.; Sarmento-Cabral, André; Olmos, David; Eyras Jiménez, Eduardo; Castaño, Justo P.; Gahete, Manuel D.; Luque, Raul M.

Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes

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dc.contributor.author Jiménez-Vacas, Juan M.
dc.contributor.author Montero-Hidalgo, Antonio J.
dc.contributor.author Gómez-Gómez, Enrique
dc.contributor.author Sáez-Martínez, Prudencio
dc.contributor.author Fuentes-Fayos, Antonio C.
dc.contributor.author Closa, Adrià
dc.contributor.author González-Serrano, Teresa
dc.contributor.author Martínez-López, Ana
dc.contributor.author Sánchez-Sánchez, Rafael
dc.contributor.author López-Casas, Pedro P.
dc.contributor.author Sarmento-Cabral, André
dc.contributor.author Olmos, David
dc.contributor.author Eyras Jiménez, Eduardo
dc.contributor.author Castaño, Justo P.
dc.contributor.author Gahete, Manuel D.
dc.contributor.author Luque, Raul M.
dc.date.accessioned 2023-02-15T07:33:15Z
dc.date.available 2023-02-15T07:33:15Z
dc.date.issued 2023
dc.description.abstract Prostate cancer (PCa) is one of the leading causes of cancer-related deaths among men. Consequently, the identification of novel molecular targets for treatment is urgently needed to improve patients' outcomes. Our group recently reported that some elements of the cellular machinery controlling alternative-splicing might be useful as potential novel therapeutic tools against advanced PCa. However, the presence and functional role of RBM22, a key spliceosome component, in PCa remains unknown. Therefore, RBM22 levels were firstly interrogated in 3 human cohorts and 2 preclinical mouse models (TRAMP/Pbsn-Myc). Results were validated in in silico using 2 additional cohorts. Then, functional effects in response to RBM22 overexpression (proliferation, migration, tumorspheres/colonies formation) were tested in PCa models in vitro (LNCaP, 22Rv1, and PC-3 cell-lines) and in vivo (xenograft). High throughput methods (ie, RNA-seq, nCounter PanCancer Pathways Panel) were performed in RBM22 overexpressing cells and xenograft tumors. We found that RBM22 levels were down-regulated (mRNA and protein) in PCa samples, and were inversely associated with key clinical aggressiveness features. Consistently, a gradual reduction of RBM22 from non-tumor to poorly differentiated PCa samples was observed in transgenic models (TRAMP/Pbsn-Myc). Notably, RBM22 overexpression decreased aggressiveness features in vitro, and in vivo. These actions were associated with the splicing dysregulation of numerous genes and to the downregulation of critical upstream regulators of cell-cycle (i.e., CDK1/CCND1/EPAS1). Altogether, our data demonstrate that RBM22 plays a critical pathophysiological role in PCa and invites to suggest that targeting negative regulators of RBM22 expression/activity could represent a novel therapeutic strategy to tackle this disease.
dc.description.sponsorship This research was funded by the Spanish Ministry of Science, Innovation, and Universities (Research‐Grant: PID2019‐105564RB‐I00; Predoctoral contracts: FPU16/05059, FPU17/00263, FPU18/02485), Health Institute Carlos III (DTS20-00050), Junta de Andalucia [BIO-0139; Consejería de Transformación Económica, Industria, Conocimiento y Universidades (P20_00442); Consejería de Salud y Familias, co-funded by European Union (Programa Operativo FEDER de Andalucía 2014-2020, “Andalucía se mueve con Europa”: PEER-0048-2020)], and CIBERobn (CIBER is an initiative of Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain). Funding for open access charge: University of Córdoba/CBUA. Some images were taken from Servier Medical Art (smart.servier.com) under the Creative Commons Attribution 3.0 Unported License. Special thanks to the staff of Biobank of the IMIBIC and of the experimental animal service (SAE) of the UCO/IMIBIC. We are gratefully indented to all the patients and their families for generously donating the samples and clinical data for research purposes. All authors have read the journal's authorship agreement.
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dc.identifier.citation Jiménez-Vacas JM, Montero-Hidalgo AJ, Gómez-Gómez E, Sáez-Martínez P, Fuentes-Fayos AC, Closa A, González-Serrano T, Martínez-López A, Sánchez-Sánchez R, López-Casas PP, Sarmento-Cabral A, Olmos D, Eyras E, Castaño JP, Gahete MD, Luque RM. Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes. Transl Res. 2023 Mar;253:68-79. DOI: 10.1016/j.trsl.2022.08.016
dc.identifier.doi http://dx.doi.org/10.1016/j.trsl.2022.08.016
dc.identifier.issn 1931-5244
dc.identifier.uri http://hdl.handle.net/10230/55785
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Transl Res. 2023 Mar;253:68-79
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019‐105564RB‐I00
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/bync-nd/4.0/
dc.title Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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