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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...

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Autores principales: Urbanski, Laura, Brugiolo, Mattia, Park, SungHee, Angarola, Brittany L., Leclair, Nathan K., Yurieva, Marina, Palmer, Phil, Sahu, Sangram Keshari, Anczuków, Olga
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
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.
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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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