Back to Search Start Over

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

Authors :
Haritha Mathsyaraja
Jonathen Catchpole
Brian Freie
Emily Eastwood
Ekaterina Babaeva
Michael Geuenich
Pei Feng Cheng
Jessica Ayers
Ming Yu
Nan Wu
Sitapriya Moorthi
Kumud R Poudel
Amanda Koehne
William Grady
A McGarry Houghton
Alice H Berger
Yuzuru Shiio
David MacPherson
Robert N Eisenman
Source :
eLife, Vol 10 (2021)
Publication Year :
2021
Publisher :
eLife Sciences Publications Ltd, 2021.

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.

Details

Language :
English
ISSN :
2050084X
Volume :
10
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.444f5d17b9d4890b2bf40c9a7a0bd54
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.64212