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MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors
MYC is dysregulated in >50% of cancers, but direct targeting of MYC has been clinically unsuccessful. Targeting downstream MYC effector pathways represents an attractive alternative. MYC regulates alternative mRNA splicing, but the mechanistic links between MYC and the splicing machinery in cance...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9731204/ https://www.ncbi.nlm.nih.gov/pubmed/36417849 http://dx.doi.org/10.1016/j.celrep.2022.111704 |
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author | Urbanski, Laura Brugiolo, Mattia Park, SungHee Angarola, Brittany L. Leclair, Nathan K. Yurieva, Marina Palmer, Phil Sahu, Sangram Keshari Anczuków, Olga |
author_facet | Urbanski, Laura Brugiolo, Mattia Park, SungHee Angarola, Brittany L. Leclair, Nathan K. Yurieva, Marina Palmer, Phil Sahu, Sangram Keshari Anczuków, Olga |
author_sort | Urbanski, Laura |
collection | PubMed |
description | MYC is dysregulated in >50% of cancers, but direct targeting of MYC has been clinically unsuccessful. Targeting downstream MYC effector pathways represents an attractive alternative. MYC regulates alternative mRNA splicing, but the mechanistic links between MYC and the splicing machinery in cancer remain under-explored. Here, we identify a network of co-expressed splicing factors (SF-modules) in MYC-active breast tumors. Of these, one is a pan-cancer SF-module correlating with MYC activity across 33 tumor types. In mammary cell models, MYC activation leads to co-upregulation of pan-cancer module SFs and to changes in >4,000 splicing events. In breast cancer organoids, co-overexpression of the pan-cancer SF-module induces MYC-regulated splicing events and increases organoid size and invasiveness, while knockdown decreases organoid size. Finally, we uncover a MYC-activity pan-cancer splicing signature correlating with survival across tumor types. Our findings provide insight into the mechanisms of MYC-regulated splicing and for the development of therapeutics for MYC-driven tumors. |
format | Online Article Text |
id | pubmed-9731204 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-97312042022-12-08 MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors Urbanski, Laura Brugiolo, Mattia Park, SungHee Angarola, Brittany L. Leclair, Nathan K. Yurieva, Marina Palmer, Phil Sahu, Sangram Keshari Anczuków, Olga Cell Rep Article MYC is dysregulated in >50% of cancers, but direct targeting of MYC has been clinically unsuccessful. Targeting downstream MYC effector pathways represents an attractive alternative. MYC regulates alternative mRNA splicing, but the mechanistic links between MYC and the splicing machinery in cancer remain under-explored. Here, we identify a network of co-expressed splicing factors (SF-modules) in MYC-active breast tumors. Of these, one is a pan-cancer SF-module correlating with MYC activity across 33 tumor types. In mammary cell models, MYC activation leads to co-upregulation of pan-cancer module SFs and to changes in >4,000 splicing events. In breast cancer organoids, co-overexpression of the pan-cancer SF-module induces MYC-regulated splicing events and increases organoid size and invasiveness, while knockdown decreases organoid size. Finally, we uncover a MYC-activity pan-cancer splicing signature correlating with survival across tumor types. Our findings provide insight into the mechanisms of MYC-regulated splicing and for the development of therapeutics for MYC-driven tumors. 2022-11-22 /pmc/articles/PMC9731204/ /pubmed/36417849 http://dx.doi.org/10.1016/j.celrep.2022.111704 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Urbanski, Laura Brugiolo, Mattia Park, SungHee Angarola, Brittany L. Leclair, Nathan K. Yurieva, Marina Palmer, Phil Sahu, Sangram Keshari Anczuków, Olga MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors |
title | MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors |
title_full | MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors |
title_fullStr | MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors |
title_full_unstemmed | MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors |
title_short | MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors |
title_sort | myc regulates a pan-cancer network of co-expressed oncogenic splicing factors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9731204/ https://www.ncbi.nlm.nih.gov/pubmed/36417849 http://dx.doi.org/10.1016/j.celrep.2022.111704 |
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