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

Haritha Mathsyaraja,Brian Freie,Alice H Berger,William Grady,David Macpherson,Sitapriya Moorthi,Kumud R Poudel,Jessica Ayers,Nan Wu,Emily Eastwood,A Mcgarry Houghton,Jonathen Catchpole,Ming Yu,Robert N Eisenman,Ekaterina Babaeva,Yuzuru Shiio,Amanda Koehne,Michael Geuenich,Pei Feng Cheng

doi:10.7554/elife.64212

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.

Highlights

Malignant progression often results from the de-regulation of factors that drive normal developmental programs
Available datasets had indicated a correlation between deletion or truncating mutations of several members of the proximal MYC network and tumor progression in lung cancer
Knockdown of either gene led to a substantial reduction in cell growth and this effect was more pronounced in sgMGA cells (Figure 7L). These results indicate that the changes we observed in mouse models, including the upregulation of MYC and ncPRC1.6 targets upon MGA loss, are consistent with those observed in patient data and human lung cancer lines

Summary

Introduction

Malignant progression often results from the de-regulation of factors that drive normal developmental programs. Given the critical role of transcription factors in the control of development and in driving cellular functions, it is not surprising that transcriptional regulators can function as potent tumor suppressors or oncogenes. A large body of evidence suggests that MYC does not function in isolation: it is part of a larger network of transcription factors that cooperate with or antagonize MYC activity (reviewed in Carroll et al, 2018).

Objectives

Results

Conclusion