Biochemical Perspectives On Targeting Kmt2 Methyltransferases In Cancer

KMT2 methyltransferases are important regulators of gene transcription through the methylation of histone H3 lysine 4 at promoter and enhancer regions. They reside in large, multisubunit protein complexes, which not only regulate their catalytic activities but also mediate their interactions with chromatin. The KMT2 family was initially associated with cancer due to the discovery of KMT2A translocations in mixed-lineage leukemia (MLL). However, emerging evidences suggest that the methyltransferase activity of KMT2 enzymes can also be important in cancer, raising the prospect of targeting the catalytic domain of KMT2 as a therapeutic strategy. In this review, we summarize recent advances in our understanding of KMT2 enzyme mechanisms and their regulation on nucleosomes, which will provide mechanistic insights into therapeutic discoveries targeting their methyltransferase activities.