MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors.
Cell Rep
; 41(8): 111704, 2022 11 22.
Article
em En
| MEDLINE
| ID: mdl-36417849
ABSTRACT
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 underexplored. 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oncogenes
/
Neoplasias da Mama
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos