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Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness

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...

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Detalles Bibliográficos
Autores principales: Mathsyaraja, Haritha, Catchpole, Jonathen, Freie, Brian, Eastwood, Emily, Babaeva, Ekaterina, Geuenich, Michael, Cheng, Pei Feng, Ayers, Jessica, Yu, Ming, Wu, Nan, Moorthi, Sitapriya, Poudel, Kumud R, Koehne, Amanda, Grady, William, Houghton, A McGarry, Berger, Alice H, Shiio, Yuzuru, MacPherson, David, Eisenman, Robert N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266391/
https://www.ncbi.nlm.nih.gov/pubmed/34236315
http://dx.doi.org/10.7554/eLife.64212
Descripción
Sumario: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.