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

Autor:	Mathsyaraja H; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Catchpole J; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Freie B; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Eastwood E; Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, United States., Babaeva E; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Geuenich M; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Cheng PF; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Ayers J; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Yu M; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Wu N; Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, United States., Moorthi S; Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, United States., Poudel KR; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Koehne A; Comparative Pathology, Fred Hutchinson Cancer Research Center, Seattle, United States., Grady W; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States.; Department of Medicine, University of Washington School of Medicine, Seattle, United States., Houghton AM; 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., Berger AH; Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, United States., Shiio Y; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, United States., MacPherson D; Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, United States., Eisenman RN; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Jul 08; Vol. 10. Date of Electronic Publication: 2021 Jul 08.
DOI:	10.7554/eLife.64212
Abstrakt:	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. Competing Interests: HM, JC, BF, EE, EB, MG, PC, JA, MY, NW, SM, KP, AK, WG, AH, AB, YS, DM No competing interests declared, RE Scientific Advisory Board Member: Kronos Bio Inc.; Shenogen Pharma Beijing. No overlap with the present study. (© 2021, Mathsyaraja et al.)
Databáze:	MEDLINE
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