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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-02-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3001138 |
| _version_ | 1829497315784654848 |
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| author | Sarah A Head Xavier Hernandez-Alias Jae-Seong Yang Ludovica Ciampi Violeta Beltran-Sastre Antonio Torres-Méndez Manuel Irimia Martin H Schaefer Luis Serrano |
| author_facet | Sarah A Head Xavier Hernandez-Alias Jae-Seong Yang Ludovica Ciampi Violeta Beltran-Sastre Antonio Torres-Méndez Manuel Irimia Martin H Schaefer Luis Serrano |
| author_sort | Sarah A Head |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-16T07:48:58Z |
| format | Article |
| id | doaj.art-76df6cb1b2ea420c84a74a8d5bee3d8b |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-16T07:48:58Z |
| publishDate | 2021-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-76df6cb1b2ea420c84a74a8d5bee3d8b2022-12-21T22:38:54ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852021-02-01192e300113810.1371/journal.pbio.3001138Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers.Sarah A HeadXavier Hernandez-AliasJae-Seong YangLudovica CiampiVioleta Beltran-SastreAntonio Torres-MéndezManuel IrimiaMartin H SchaeferLuis SerranoRNA 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.https://doi.org/10.1371/journal.pbio.3001138 |
| spellingShingle | Sarah A Head Xavier Hernandez-Alias Jae-Seong Yang Ludovica Ciampi Violeta Beltran-Sastre Antonio Torres-Méndez Manuel Irimia Martin H Schaefer Luis Serrano Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers. PLoS Biology |
| 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 |
| url | https://doi.org/10.1371/journal.pbio.3001138 |
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