期刊
MOLECULAR CANCER RESEARCH
卷 18, 期 4, 页码 574-584出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-19-0657
关键词
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资金
- Lung Cancer Research Foundation Fund
- 2015 AACR-John and Elizabeth Leonard Family Foundation Basic Cancer Research Fellowship
- NCI [R35CA197568]
- Norman R. Seaman Endowment Fund
- Spain MINECO [SAF-2014-54571-R, BES-2015-072204]
- Fundacion Cientifica Asociacion Espanola Contra el Cancer grant [GCB14-2170]
- NCI Clinical Proteomic Tumor Analysis Consortium grants [NIH/NCI U24-CA210986, NIH/NCI U01 CA214125]
- European Association for Cancer Research Travel fellowship
Genomic analysis of lung adenocarcinomas has revealed that the MGA 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.
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