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

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.

Normal and Neoplastic Growth Suppression by The Extended Myc Network

“…The above findings were extended to normal colonic epithelium and colo-rectal cancer, in which MGA is frequently mutated or deleted (Fig. 2) [337]. In the former case, CRISPR-mediated MGA inactivation in colon organoids was associated with reduced levels of L3mbtl2 and an increased rate of 3D growth in vitro.…”

“…In addition to the above and other reports in CLL, MGA inactivation, mostly involving terminating mutations or gene deletion (and nearly always hemizygous), have been described in as many as 10-20% of a variety of cancers including retinoblastomas, sporadic colo-rectal cancers, gastroenteropancreatic neuroendocrine tumors, gastrointestinal stromal cell tumors, lung squamous cell and adenocarcinomas, head and neck cancers and acute myelogenous leukemias (AML) [93,104,327,[331][332][333][334][335][336][337][338][339][340][341][342]. Silencing Mga in an AML cell line increased both its in vitro colony formation and its growth rate [340].…”

“…A more recent study of Mga function in cancer that expanded upon the above results indicated that CRISPR-mediated Mga inactivation accelerated tumor growth and shortened survival in both the KrasLSL-G12D and KrasLSL-G12D+Tp53-/models of lung cancer [335,337]. While this indicated that Mga loss facilitated the growth of tumors in highly susceptible hosts, it was not determined whether Mga inactivation in otherwise normal mice impacted spontaneous tumor growth as happens with more traditional TSs such as TP53 or Mlx [63,[352][353][354].…”

“…A recently performed ChIPseq survey identify the genomic sites occupied for Myc, Max, Mga, L3MBTL2, E2F6 and phosphorylated RNA pol II in Mga-replete and Mga-knockout KrasLSL-G12D+Tp53-/-tumor cells [337]. Components of the Mga-PRC1.6 complex (i.e.…”

Polycomb group proteins in cancer: multifaceted functions and strategies for modulation

“…MGA mutations are frequently found in multiple cancer types (Figure 3 ). The oncogenic role of MGA mutation is likely not due to the loss of PRC1.6 function but instead due to the release of free MAX, which can associate with MYC, and facilitate MYC-mediated oncogenic transcription ( 117 , 118 ). Whether mutations in other PRC1.6 subunits affect MYC function in a similar manner has not been established.…”