Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness.
Elife
; 102021 07 08.
Article
em En
| MEDLINE
| ID: mdl-34236315
ABSTRACT
MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR-based approach. MGA loss significantly accelerated tumor growth in both models and led to de-repression of non-canonical Polycomb ncPRC1.6 targets, including genes involved in metastasis and meiosis. Moreover, MGA deletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA-MAX, E2F6, and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes these ncPRC1.6 subunits. Lastly, we report that MGA loss also induces a pro-growth effect in human colon organoids. Our studies establish MGA as a bona fide tumor suppressor in vivo and suggest a tumor suppressive mechanism in adenocarcinomas resulting from widespread transcriptional attenuation of MYC and E2F target genes mediated by MGA-MAX associated with a non-canonical Polycomb complex.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Pulmonar de Células não Pequenas
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Fatores de Transcrição Hélice-Alça-Hélice Básicos
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Proteínas do Grupo Polycomb
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Repressão Epigenética
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article