PIK3CA and cancer: AKT indirectly increases promoter H3K4me3 through the inactivation of the H3K4 demethylase KDM5A (6), and when coupled with AKT phosphorylation of KMT2D/MLL4, these studies suggest at least two mechanisms by which PI3K/AKT signaling modulates H3K4-driven epigenetic plasticity to contribute to cancer development and therapeutic response.