3090 – KDM4A/C SUSTAIN AN ONCOGENIC PROGRAM BY EPIGENETIC REWIRING OF ONCOGENIC AND LINEAGE ENHANCERS

Many prior studies have focused on the role of mutations in epigenetic factors in cancer (e.g., EZH2, CREBBP, EP300, KMT2C, KMT2D) but drugs targeting these mutations have shown only modest activity in patients. Here we identify overexpression of KDM4A and KDM4C, two erasers of histone H3K9 methylation in multiple cancers, and demonstrate that their misexpression in lymphoma and colorectal cancer results in low H3K9me2/3 over pro-oncogenic transcription factor binding sites (TFBS) present in the vicinity of endogenous retro-elements (EREs). Consistently, KDM4A/4C inhibition results in the reallocation of H3K9me2/3 and H3K27Ac over enhancers, leading to activation of intracellular nucleic acid-sensing, and repression of the Wnt/beta-catenin transcriptional program. Our integrative epigenomic and transcriptomic analysis revealed a geneset that risk-stratified both lymphoma and colorectal cancer patients. We propose that high levels of H3K9me2/3 in somatic cells maintain genome stability and lineage-fidelity by repressing EREs and associated oncogenic enhancers, and that reduction of H3K9me2/3 from these regions is a prerequisite for oncogenesis. Our study establishes KDM4A and KDM4C as relevant anti-cancer targets in lymphoma and Wnt-dependent cancers and suggests that modulating innate immunity through dynamic regulation of H3K9 methylation can be leveraged for anti-cancer therapy.