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

TL;DR

This study explores how changes in hexokinase 2 expression affect chromatin stability and epigenetic inheritance in yeast.

Contribution

The study reveals that HXK2 is dominant in yeast growth and that 2-DG increases chromatin instability independently of HXK2.

Findings

HXK2 is the dominant hexokinase in yeast cell growth.

2-deoxy-D-glucose treatment increases chromatin instability independently of HXK2.

Alternative hexokinases like HXK1 or GLK1 maintain epigenomic stability when HXK2 is absent.

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 DNA and histones in cells, we hypothesized that altering
HK2
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 (
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 demonstrated 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
HK2
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 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.