You are here

Mol Cancer Res DOI:10.1158/1541-7786.MCR-19-0657

Multi-Omics Analysis Identifies MGA as a Negative Regulator of the MYC Pathway in Lung Adenocarcinoma.

Publication TypeJournal Article
Year of Publication2020
AuthorsLlabata, P, Mitsuishi, Y, Choi, PS, Cai, D, Francis, JM, Torres-Diz, M, Udeshi, ND, Golomb, L, Wu, Z, Zhou, J, Svinkina, T, Aguilera-Jimenez, E, Liu, Y, Carr, SA, Sanchez-Cespedes, M, Meyerson, M, Zhang, X
JournalMol Cancer Res
Date Published2020 04

Genomic analysis of lung adenocarcinomas has revealed that the gene, which encodes a heterodimeric partner of the MYC-interacting protein MAX, is significantly mutated or deleted in lung adenocarcinomas. Most of the mutations are loss of function for MGA, suggesting that MGA may act as a tumor suppressor. Here, we characterize both the molecular and cellular role of MGA in lung adenocarcinomas and illustrate its functional relevance in the MYC pathway. Although MGA and MYC interact with the same binding partner, MAX, and recognize the same E-box DNA motif, we show that the molecular function of MGA appears to be antagonistic to that of MYC. Using mass spectrometry-based affinity proteomics, we demonstrate that MGA interacts with a noncanonical PCGF6-PRC1 complex containing MAX and E2F6 that is involved in gene repression, while MYC is not part of this MGA complex, in agreement with previous studies describing the interactomes of E2F6 and PCGF6. Chromatin immunoprecipitation-sequencing and RNA sequencing assays show that MGA binds to and represses genes that are bound and activated by MYC. In addition, we show that, as opposed to the MYC oncoprotein, MGA acts as a negative regulator for cancer cell proliferation. Our study defines a novel MYC/MAX/MGA pathway, in which MYC and MGA play opposite roles in protein interaction, transcriptional regulation, and cellular proliferation. IMPLICATIONS: This study expands the range of key cancer-associated genes whose dysregulation is functionally equivalent to activation and places MYC within a linear pathway analogous to cell-cycle or receptor tyrosine kinase/RAS/RAF pathways in lung adenocarcinomas.


Alternate JournalMol. Cancer Res.
PubMed ID31862696
Grant ListU24 CA210986 / CA / NCI NIH HHS / United States
U01 CA214125 / CA / NCI NIH HHS / United States