Novel Functions of Lysine Demethylases as Mitochondrial Gatekeepers

There is considerable evidence that KDMs, lysine demethylases, are oncogenic drivers for cancers. We have focused on KDM4A (Wang et al., Cell Reports, 2016) and KDM8 (Wang et al., PNAS, 2014) in prostate carcinogenesis. Both KDM4A and KDM8 are overexpressed in prostate cancers and their overexpressions confer castration-resistance as well as therapy-resistance. KDM4A demethylates H3K9me3 and H3K36me2/3, whereas KDM8 demethylates H3K36me2 (Hsia et al., PNAS, 2010). They both are coactivators of AR and when overexpressed, activate androgen response genes. Here, we report that they have additional novel functions as the gate keepers of mitochondria. Pyruvate flow into mitochondria is important for TCA cycle and oxidative phosphorylation, which is regulated by two key kinases PKM2 (pyruvate kinase M2) and PDKs (pyruvate dehydrogenase kinases). Cytosolic PKM2, the predominant form in tumor cells, is responsible for the synthesis of pyruvate, the level of which dictates the flow to mitochondria or to lactate. PDK1 to 4 negatively regulate the conversion of pyruvate to acetyl-coA by phosphorylating pyruvate dehydrogenase. We have shown that KDM8 associates with PKM2 and effectively translocates PKM2 into the nucleus, where KDM8/PKM2 serve as coactivator of HIF-1a. The consequence of this translocation is the decrease of cytosolic PKM2 activity and the increase of the expression of glycolytic enzymes, resulting in the limited pyruvate flow into mitochondria. At the same time, it favors the anabolic pathways and the biosynthesis of macromolecules, required for metabolic adaptation of tumor cells. KDM4, as we reported recently, serves as an E2F1 coactivator enhances the expression of PDK1 and PDK3, which also limits the flow of pyruvate to acetyl-coA and oxidative phosphorylation. Thus, both KDM8 and KDM4A work in concert to deflect pyruvate from mitochondria in favor of tumor metabolism. The detailed mechanisms and their implications in cancer therapies will be discussed.