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M. Torres-Diz
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-086 - MGA Suppresses the MYC Pathway in Lung Adeocarcinoma (ID 8022)
09:30 - 09:30 | Author(s): M. Torres-Diz
- Abstract
Background:
Recent exome-sequencing efforts have revealed that the MGA gene, which encodes a heterodimeric partner of the MYC-interacting protein MAX, is significantly mutated (~8%) in lung adenocarcinomas. Most MGA mutations are loss-of-function, suggesting that MGA may act as a tumor suppressor. MGA mutations are mutually exclusive to MYC gene amplification, suggesting the involvement of MGA in the MYC pathway. Here, we aimed to characterize both the cellular and molecular role of MGA in lung adenocarcinoma, with a focus on studying its role in modulating the MYC pathway.
Method:
Chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) analysis were used to identify MYC and MGA DNA binding sites and binding motifs. Inmunoprecipitation assays and mass spectrometry were used to elucidate MGA gene repression mechanism. Cell competition assay was performed to measure cell proliferation with and without MGA overexpression. Finally, electrophoretic mobility shift assays (EMSA) were used to functionally evaluate MGA DNA binding ability to E-boxes when missense mutations in the basic-Helix-Loop-Helix (bHLH) domain of MGA occur.
Result:
We found that ectopic expression of wild-type MGA represses the cellular growth of lung adenocarcinoma cell lines. Chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) analyses revealed that MGA recognizes the same DNA binding motif as MYC, shares a large proportion of genomic DNA binding sites with MYC, and represses expression of MYC target genes. Immunoprecipitation assays in combination with mass spectrometry analysis reported that MGA interacts with several gene repressing proteins and complexes, such as the Polycomb repressive complex 1 (PRC1), histone deacetylases HDAC1/2, and the E2F6 transcriptional repressor, suggesting a potential mechanism by which MGA represses its target genes. In addition, we analyzed the mutation profile of MGA on a pan-cancer scale, revealing recurrent missense mutations in the basic-Helix-Loop-Helix (bHLH) domain of MGA in other cancer types such as colorectal and endometrial carcinomas. Electrophoretic mobility shift assays (EMSA) showed that these missense mutations impair the DNA binding ability of MGA, suggesting that these missense mutations, in addition to truncation mutations, disrupt the function of MGA in cancer cells.
Conclusion:
In summary, our results suggest that MGA plays a tumor suppressor role by binding to and repressing MYC target genes, thus expanding our current knowledge of genomic mechanisms for MYC pathway activation in cancer.
