Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers

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  • dc.contributor.author Head, Sarah A.
  • dc.contributor.author Hernandez-Alias, Xavier
  • dc.contributor.author Yang, Jae-Seong
  • dc.contributor.author Ciampi, Ludovica
  • dc.contributor.author Beltran-Sastre, Violeta
  • dc.contributor.author Torres Méndez, Antonio, 1992-
  • dc.contributor.author Irimia Martínez, Manuel
  • dc.contributor.author Schaefer, Martin H.
  • dc.contributor.author Serrano Pubull, Luis, 1982-
  • dc.date.accessioned 2021-03-23T11:10:49Z
  • dc.date.available 2021-03-23T11:10:49Z
  • dc.date.issued 2021
  • dc.description.abstract RNA splicing is widely dysregulated in cancer, frequently due to altered expression or activity of splicing factors (SFs). Microexons are extremely small exons (3-27 nucleotides long) that are highly evolutionarily conserved and play critical roles in promoting neuronal differentiation and development. Inclusion of microexons in mRNA transcripts is mediated by the SF Serine/Arginine Repetitive Matrix 4 (SRRM4), whose expression is largely restricted to neural tissues. However, microexons have been largely overlooked in prior analyses of splicing in cancer, as their small size necessitates specialized computational approaches for their detection. Here, we demonstrate that despite having low expression in normal nonneural tissues, SRRM4 is further silenced in tumors, resulting in the suppression of normal microexon inclusion. Remarkably, SRRM4 is the most consistently silenced SF across all tumor types analyzed, implying a general advantage of microexon down-regulation in cancer independent of its tissue of origin. We show that this silencing is favorable for tumor growth, as decreased SRRM4 expression in tumors is correlated with an increase in mitotic gene expression, and up-regulation of SRRM4 in cancer cell lines dose-dependently inhibits proliferation in vitro and in a mouse xenograft model. Further, this proliferation inhibition is accompanied by induction of neural-like expression and splicing patterns in cancer cells, suggesting that SRRM4 expression shifts the cell state away from proliferation and toward differentiation. We therefore conclude that SRRM4 acts as a proliferation brake, and tumors gain a selective advantage by cutting off this brake.
  • dc.description.sponsorship Funding: This project was funded in part by a grant from the Plan Estatal de Investigación Científica y Técnica y de Innovación to L.S. (PGC2018-101271-B-I00, http://www.ciencia.gob.es). S.A.H. is supported by a Marie Skłodowska-Curie Individual Fellowship from the European Union’s Horizon 2020 research and innovation programme (MSCA-IF-2017-794629, http://ec.europa.eu/). X.H. is supported by a PhD fellowship from the Fundación Ramón Areces (http://www.fundacionareces.es). We acknowledge the support of the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa’, the CERCA Programme / Generalitat de Catalunya, and the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Head SA, Hernandez-Alias X, Yang JS, Ciampi L, Beltran-Sastre V, Torres-Méndez A et al. Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers. PLoS Biol. 2021 Feb 23; 19(2): e3001138. DOI: 10.1371/journal.pbio.3001138
  • dc.identifier.doi http://dx.doi.org/10.1371/journal.pbio.3001138
  • dc.identifier.issn 1544-9173
  • dc.identifier.uri http://hdl.handle.net/10230/46907
  • dc.language.iso eng
  • dc.publisher Public Library of Science (PLoS)
  • dc.relation.ispartof PLOS Biology. 2021 Feb 23;19(2):e3001138
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/794629
  • dc.rights © 2021 Head et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.other Càncer
  • dc.subject.other Tumors
  • dc.subject.other Genètica
  • dc.title Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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