The Role of Hexokinases in Epigenetic Regulation: Altered Hexokinase Expression and Chromatin Stability in Yeast.

. Human hexokinase 2 ( ) plays an important role in regulating Warburg effect, which metabolizes glucose to lactate acid even in the presence of ample oxygen and provides intermediate metabolites to support cancer cell proliferation and tumor growth. overexpression has been observed in various types of cancers and targeting -driven Warburg effect has been suggested as a potential cancer therapeutic strategy. Given that epigenetic enzymes utilize metabolic intermediates as substrates or co-factors to carry out post-translational modification of DNA and histones in cells, we hypothesized that altering expression-mediated cellular glycolysis rates could impact the epigenome and, consequently, genome stability in yeast. To test this hypothesis, we established genetic models with different yeast hexokinase 2 ( expression in yeast cells and investigated the effect of -dependent metabolism on parental nucleosome transfer, a key DNA replication-coupled epigenetic inheritance process, and chromatin stability. . By comparing the growth of mutant yeast cells carrying single deletion of , , or double-loss of to wild-type cells, we demonstrated that is the dominant in yeast cell growth. Surprisingly, manipulating expression in yeast, whether through overexpression or deletion, had only a marginal impact on parental nucleosome assembly, but a noticeable trend with decrease chromatin instability. However, targeting yeast cells with 2-deoxy-D-glucose (2-DG), a inhibitor that has been proposed as an anti-cancer treatment, significantly increased chromatin instability. . Our findings suggest that in yeast cells lacking , alternative s such as or glucokinase 1 ( ) play a role in supporting glycolysis at a level that adequately maintain epigenomic stability. While our study demonstrated an increase in epigenetic instability with 2-DG treatment, the observed effect seemed to occur independently of Hxk2-mediated glycolysis inhibition. Thus, additional research is needed to identify the molecular mechanism through which 2-DG influences chromatin stability.