MYC interacts with the G9a histone methyltransferase to drive transcriptional repression and tumorigenesis. MYC interacts with the G9a histone methyltransferase to drive transcriptional repression and tumorigenesis

MYC is an oncogenic driver that regulates transcriptional activation and repression, yet molecular mechanisms of MYC transformation remain unclear. We demonstrate that MYC interacts with the G9a H3K9-methyltransferase complex to control transcriptional repression. Inhibiting G9a hinders MYC chromatin binding at MYC-repressed genes and de-represses gene expression to antagonize cellular transformation. By identifying the MYC Box II region as essential for MYC-G9a interaction, a long-standing missing link between MYC transformation and gene repression is unveiled. In breast cancer, anti-proliferative sensitivity to G9a pharmacological inhibition associates with MYC sensitivity and the basal subtype. Inhibiting G9a in vivo suppresses MYC-dependent basal breast tumor growth. Our findings reveal G9a as an epigenetic regulator of MYC-mediated transcriptional repression and a therapeutic vulnerability in MYC-driven cancers. Overall design: Transcriptome-wide analysis comparing the effect of G9a knockdown (using two independent shRNAs) versus scramble control (shSCR) in MCF10A breast epithelial cells transformed with ectopic PI3KH1047R and MYC (MCF10A.PM). Three biological replicates for each shRNA condition was performed.