MYC Interacts with the G9a Methyltransferase to Repress Target Genes

MYC is dysregulated in the majority of tumors, where it regulates transcriptional activation and repression to drive oncogenesis. The mechanisms by which MYC promotes transcriptional repression remain incompletely understood. MYC interacts with the transcription factor MIZ1, and this interaction underlies MYC-mediated repression of a subset of target genes. However, the factors that contribute to MYC-mediated transcriptional repression in the absence of MIZ1 are not understood. Through an in-cell biotin-labeling mass spectrometry technique, Tu and colleagues identified the G9a methyltransferase complex as a putative MYC interactor, and further investigated its role in controlling MYC-mediated transcription and tumorigenesis. Indeed, MYC interacted with G9a in breast cancer cells and regulated dimethylation of histone 3 lysine 9 (H3K9me2). MYC depletion reduced global levels of H3K9me2. Chromatin immunoprecipitation revealed that G9a binds to MYC at MYC-repressed target genes, cooperating with MYC to repress transcription. Depleting G9a preferentially reduced MYC binding at repressed target genes, thereby increasing their expression. These genes displayed decreased H3K9me2 upon G9a depletion with elevation of H3K9me1 and H3K9ac, indicating that G9a depletion shifts transcriptionally repressed H3K9me2 marked chromatin to a transcriptionally active state. The interaction between MYC and G9a required the MYC Box II domain, which is essential for MYC-driven transformation, but was independent of the MIZ1 interaction. Small-molecule inhibition of G9a reduced the anchorage-independent growth of MYC-dependent breast cancer cell lines in vitro and reduced H3K9me2 and MYC binding at MYC-repressed promoters, but the growth of MYC-independent breast cancer cells was not affected. In vivo, G9a inhibition reduced the growth of MYC-dependent breast cancer xenografts. Collectively, these findings reveal that G9a interacts with MYC to promote repression of MYC target genes, suggesting the potential for therapeutic targeting of G9a in MYC-dependent breast cancer.

Tu WB, Shiah YJ, Lourenco C, Mullen PJ, Dingar D, Redel C, et al. MYC Interacts with the G9a histone methyltransferase to drive transcriptional repression and tumorigenesis. Cancer Cell 2018;34:579–95.

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