The role of hexokinases in epigenetic regulation: altered hexokinase expression and chromatin stability in yeast

Abstract                                        Background                                            Human hexokinase 2 (HK2) 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.                       HK2                       overexpression has been observed in various types of cancers and targeting                       HK2                       -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 histones and nucleic acids modifications in cells, we hypothesized that altering                       HK2                       expression could impact the epigenome and, consequently, chromatin stability in yeast. To test this hypothesis, we established genetic models with different yeast hexokinase 2 (                       HXK2)                       expression in                       Saccharomyces cerevisiae                       yeast cells and investigated the effect of                       HXK2                       -dependent metabolism on parental nucleosome transfer, a key DNA replication–coupled epigenetic inheritance process, and chromatin stability.                                                                                Results                                            By comparing the growth of mutant yeast cells carrying single deletion of                       hxk1Δ                       ,                       hxk2Δ                       , or double-loss of                       hxk1Δ hxk2Δ                       to wild-type cells, we firstly confirmed that                       HXK2                       is the dominant                       HXK                       in yeast cell growth. Surprisingly, manipulating                       HXK2                       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 clinical glycolysis inhibitor that has been proposed as an anti-cancer treatment, significantly increased chromatin instability.                                                                                Conclusion                                            Our findings suggest that in yeast cells lacking                       HXK2                       , alternative                       HXK                       s such as                       HXK1                       or glucokinase 1 (                       GLK1                       ) play a role in supporting glycolysis at a level that adequately maintains epigenomic stability. While our study demonstrated an increase in epigenetic instability with 2-DG treatment, the observed effect seemed to occur dependent on non-glycolytic function of Hxk2. Thus, additional research is needed to identify the molecular mechanism through which 2-DG influences chromatin stability.