Loss of KMT2D induces prostate cancer ROS-mediated DNA damage by suppressing the enhancer activity and DNA binding of antioxidant transcription factor FOXO3.

Histone methyltransferase KMT2D has diverse functions and distinct mechanisms in different cancers. Although we have previously found KMT2D serves as an oncogene that promotes tumor growth and metastasis in prostate cancer (PCa), the functions and mechanisms of KMT2D are complicated and most remain undefined. Here, the function of KMT2D regarding DNA damage in PCa and the underlying mechanisms of KMT2D in epigenetic regulation were explored in a series of studies. Knockdown of KMT2D sensitized cells to DNA damage through the disturbance of antioxidative gene expression and increased levels of intracellular reactive oxygen species, which led to cell apoptosis and senescence. The loss of KMT2D reduced the abundance of enhancer activity markers H3K4me1 and H3K27ac, which blocked the DNA binding of FOXO3, a critical mediator of the cellular response to oxidative stress, and suppressed antioxidative gene transcription. Moreover, KMT2D deletion in PCa cells also increased their sensitivity to genotoxic anticancer drugs and a PARP inhibitor, which suggested that lower levels of KMT2D may mediate the response of PCa to particular treatments. These findings further highlighted the important role of KMT2D in PCa progression and suggested that targeting KMT2D might be therapeutically beneficial for advanced PCa treatment.