PT  - JOURNAL ARTICLE
AU  - Haritha Mathsyaraja
AU  - Jonathen Catchpole
AU  - Emily Eastwood
AU  - Ekaterina Babaeva
AU  - Michael Geuenich
AU  - Pei Feng Cheng
AU  - Brian Freie
AU  - Jessica Ayers
AU  - Ming Yu
AU  - Nan Wu
AU  - Kumud R Poudel
AU  - Amanda Koehne
AU  - William Grady
AU  - A McGarry Houghton
AU  - Yuzuru Shiio
AU  - David P MacPherson
AU  - Robert N Eisenman
TI  - Loss of MGA mediated Polycomb repression promotes tumor progression and invasiveness
AID  - 10.1101/2020.10.16.334714
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.16.334714
4099  - http://biorxiv.org/content/early/2020/10/17/2020.10.16.334714.short
4100  - http://biorxiv.org/content/early/2020/10/17/2020.10.16.334714.full
AB  - 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 atypical Polycomb PRC1.6, E2F and MYC-MAX targets. Similarly, MGA depletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA, E2F6 and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes PRC1.6 subunits. Lastly, we report that MGA loss has also 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 targets mediated by an atypical Polycomb complex containing MGA-MAX dimers.Competing Interest StatementRNE: Kronos Bio Inc. Advisory board honoraria, stock options