Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
CAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics and Shenzhen Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
Epigenetics Chromatin. 2024 Aug 27;17(1):27. doi: 10.1186/s13072-024-00551-9.
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.
人类己糖激酶 2（HK2）在调节瓦博格效应中起着重要作用，即使在氧气充足的情况下，它也能将葡萄糖代谢为乳酸，并为癌细胞的增殖和肿瘤的生长提供中间代谢产物。在各种类型的癌症中都观察到了 HK2 的过表达，靶向 HK2 驱动的瓦博格效应已被认为是一种潜在的癌症治疗策略。鉴于表观遗传酶利用代谢中间产物作为底物或辅助因子，在细胞中对组蛋白和核酸进行翻译后修饰，我们假设改变 HK2 的表达会影响表观基因组，进而影响酵母中的染色质稳定性。为了验证这一假设，我们在酿酒酵母细胞中建立了不同的酵母己糖激酶 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的影响，亲本核小体转移是一个关键的 DNA 复制偶联的表观遗传遗传过程，以及染色质稳定性。
通过比较携带 hxk1Δ、 hxk2Δ 单一缺失或 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 是酵母细胞生长中主要的 HXK。令人惊讶的是，在酵母中操纵 HXK2 的表达，无论是通过过表达还是缺失，对亲本核小体组装的影响都很小，但有减少染色质不稳定的明显趋势。然而，用 2-脱氧-D-葡萄糖（2-DG）靶向酵母细胞，2-DG 是一种已被提议用于癌症治疗的临床糖酵解抑制剂，显著增加了染色质的不稳定性。
我们的研究结果表明，在缺乏 HXK2 的酵母细胞中，替代的 HXKs，如 HXK1 或葡萄糖激酶 1（GLK1），在维持足够的表观基因组稳定性的水平上发挥作用，支持糖酵解。虽然我们的研究表明，用 2-DG 处理会增加表观遗传不稳定性，但观察到的效应似乎依赖于 Hxk2 的非糖酵解功能。因此，需要进一步的研究来确定 2-DG 影响染色质稳定性的分子机制。
