人己糖激酶 2 (HK2) 在调节 Warburg 效应中发挥着重要作用，即使在充足的氧气存在下，该效应也会将葡萄糖代谢为乳酸，并提供中间代谢产物以支持癌细胞增殖和肿瘤生长。 HK2 过度表达已在多种类型的癌症中观察到，并且针对 HK2 驱动的 Warburg 效应已被建议作为一种潜在的癌症治疗策略。鉴于表观遗传酶利用代谢中间体作为底物或辅助因子来进行细胞中组蛋白的翻译后修饰和核酸修饰，我们假设改变 HK2 表达可能会影响表观基因组，从而影响酵母中的染色质稳定性。为了检验这一假设，我们在酿酒酵母细胞中建立了不同酵母己糖激酶 2 (HXK2) 表达的遗传模型，并研究了 HXK2 依赖性代谢对亲本核小体转移、关键的 DNA 复制耦合表观遗传过程和染色质稳定性的影响。通过比较携带hxk1Δ、hxk2Δ单缺失或hxk1Δ hxk2Δ双缺失的突变酵母细胞与野生型细胞的生长情况，我们首先证实HXK2是酵母细胞生长中的主导HXK。令人惊讶的是，在酵母中操纵 HXK2 表达，无论是通过过表达还是缺失，对亲代核小体组装仅产生边际影响，但有明显的趋势，即染色质不稳定性降低。然而，用 2-脱氧-D-葡萄糖 (2-DG)（一种被提议作为抗癌治疗的临床糖酵解抑制剂）靶向酵母细胞，会显着增加染色质的不稳定性。我们的研究结果表明，在缺乏 HXK2 的酵母细胞中，替代品HXK1 或葡萄糖激酶 1 (GLK1) 等 HXK 在支持糖酵解方面发挥作用，其水平足以维持表观基因组稳定性。虽然我们的研究证明 2-DG 治疗会增加表观遗传不稳定性，但观察到的效果似乎依赖于 Hxk2 的非糖酵解功能。因此，需要进行更多研究来确定 2-DG 影响染色质稳定性的分子机制。© 2024。作者。

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.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.Our findings suggest that in yeast cells lacking HXK2, alternative HXKs 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.© 2024. The Author(s).