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

eLife

Brian Freie¹  Jonathen Catchpole¹  Pei Feng Cheng¹  Ekaterina Babaeva¹  Kumud R Poudel¹  Robert N Eisenman¹  Michael Geuenich¹  Haritha Mathsyaraja¹  Jessica Ayers²  Ming Yu²  William Grady³  Amanda Koehne⁴  Yuzuru Shiio⁵  David MacPherson⁶  Alice H Berger⁶  Nan Wu⁶  Emily Eastwood⁶  Sitapriya Moorthi⁶  A McGarry Houghton⁷ 

[1] Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States;Department of Medicine, University of Washington School of Medicine, Seattle, United States;Comparative Pathology, Fred Hutchinson Cancer Research Center, Seattle, United States;Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, United States;Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, United States;Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, United States;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States;

关键词: tumor suppressor;    MGA;    MAX;    non-canonical polycomb;    lung adenocarcinoma;    colon organoids;    Mouse;   

DOI  :  10.7554/eLife.64212

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY