EZH2 and cancer: Histone H4 lysine 20 trimethylation (H4K20me3) has been shown to be lost as a hallmark of human cancer [2], and is differentially decreased in p16-positive OPSCC [20] The enzyme enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase (HMT) that acts to trimethylate lysine 27 on histone H3 (H3K27me3) and its increased expression has been linked to a number of malignancies.