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

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 developme...

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Autores principales: Head, Sarah A., Hernandez-Alias, Xavier, Yang, Jae-Seong, Ciampi, Ludovica, Beltran-Sastre, Violeta, Torres-Méndez, Antonio, Irimia, Manuel, Schaefer, Martin H., Serrano, Luis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935315/
https://www.ncbi.nlm.nih.gov/pubmed/33621242
http://dx.doi.org/10.1371/journal.pbio.3001138
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author Head, Sarah A.
Hernandez-Alias, Xavier
Yang, Jae-Seong
Ciampi, Ludovica
Beltran-Sastre, Violeta
Torres-Méndez, Antonio
Irimia, Manuel
Schaefer, Martin H.
Serrano, Luis
author_facet Head, Sarah A.
Hernandez-Alias, Xavier
Yang, Jae-Seong
Ciampi, Ludovica
Beltran-Sastre, Violeta
Torres-Méndez, Antonio
Irimia, Manuel
Schaefer, Martin H.
Serrano, Luis
author_sort Head, Sarah A.
collection PubMed
description 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.
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spelling pubmed-79353152021-03-15 Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers Head, Sarah A. Hernandez-Alias, Xavier Yang, Jae-Seong Ciampi, Ludovica Beltran-Sastre, Violeta Torres-Méndez, Antonio Irimia, Manuel Schaefer, Martin H. Serrano, Luis PLoS Biol Research Article 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. Public Library of Science 2021-02-23 /pmc/articles/PMC7935315/ /pubmed/33621242 http://dx.doi.org/10.1371/journal.pbio.3001138 Text en © 2021 Head et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Head, Sarah A.
Hernandez-Alias, Xavier
Yang, Jae-Seong
Ciampi, Ludovica
Beltran-Sastre, Violeta
Torres-Méndez, Antonio
Irimia, Manuel
Schaefer, Martin H.
Serrano, Luis
Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers
title Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers
title_full Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers
title_fullStr Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers
title_full_unstemmed Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers
title_short Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers
title_sort silencing of srrm4 suppresses microexon inclusion and promotes tumor growth across cancers
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935315/
https://www.ncbi.nlm.nih.gov/pubmed/33621242
http://dx.doi.org/10.1371/journal.pbio.3001138
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