SMYD2 methylates KDM5A restricting its demethylase activity on the genome (and driving proliferation

Members of the KDM5 family of Jumonji histone demethylases have been implicated in a variety of human diseases including multiple cancers. The regulation of KDM5 enzyme levels and activity, however, is poorly understood. Here we report that KDM5A is methylated by SMYD2 and that this methylation impacts histone demethylase activity. A mutant KDM5A that can no longer be methylated at K1063 exhibits unique genomic sites of action, demethylates H3K4me3 more robustly and at new loci, has unique transcriptional effects and distinct protein-protein interactions. As a result, a number of cell proliferation pathways are affected and cancer cell growth is blunted. This study illustrates the functional consequences of post-translational modifications of lysine residues in enzymes impacting genomic histone demethylation, gene expression and signaling.