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

Autor: Brian Freie, Michael Geuenich, Alice H. Berger, Nan Wu, Sitapriya Moorthi, Jessica Ayers, A. McGarry Houghton, Ekaterina Babaeva, Pei Feng Cheng, Robert N. Eisenman, Ming Yu, Kumud R. Poudel, Yuzuru Shiio, Emily Eastwood, Amanda Koehne, William M. Grady, Jonathen Catchpole, Haritha Mathsyaraja, David MacPherson
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
colon organoids
Mouse
Polycomb-Group Proteins
law.invention
Mice
0302 clinical medicine
law
Carcinoma
Non-Small-Cell Lung
Basic Helix-Loop-Helix Transcription Factors
Biology (General)
Cancer Biology
General Neuroscience
General Medicine
030220 oncology & carcinogenesis
Disease Progression
Medicine
Adenocarcinoma
Female
Research Article
MAX
tumor suppressor
QH301-705.5
Science
Adenocarcinoma of Lung
Epigenetic Repression
Biology
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Cell Line
Tumor
medicine
Animals
Humans
Neoplasm Invasiveness
MGA
Transcriptional attenuation
E2F
Psychological repression
Transcription factor
non-canonical polycomb
General Immunology and Microbiology
Promoter
lung adenocarcinoma
medicine.disease
030104 developmental biology
Tumor progression
Cancer research
Suppressor
Zdroj: eLife, Vol 10 (2021)
eLife
ISSN: 2050-084X
Popis: 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.
Databáze: OpenAIRE
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