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

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

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Article numbere64212
JournaleLife
Volume10
DOIs
StatePublished - Jul 2021

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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