Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy

Abstract

<p class="first" id="P1">MLL3 (also named KMT2C) is a COMPASS subunit that implements H3K4 mono-methylation at gene enhancers. <i>KMT2C</i> frequently incurs point-mutations across a range of human tumors, nevertheless precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within its Plant Homeo Domain (PHD) repeats and demonstrate that this domain mediates association with the histone H2A deubiquitinase and tumor suppressor BAP1. Cancer-associated MLL3 PHD mutations disrupt the interaction between MLL3 and BAP1 and correlate with poor patient survival. Cancer cells bearing MLL3 PHD mutations or lacking BAP1, exhibit reduced enhancer recruitment of MLL3 and the H3K27 demethylase UTX (KDM6A). As the result, inhibiting the H3K27 methyltransferase activity of polycomb repressor complex 2 (PRC2) in tumor cells harboring BAP1 or MLL3 mutations, restores normal gene expression patterns and impairs cell proliferation in vivo. This study provides mechanistic insight for the role of MLL3 PHD mutations in cancer and points to restoration of the balanced state of polycomb-COMPASS for the treatment of cancers resulting from mutations in these epigenetic factors. </p>