Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Korea.
College of Pharmacy, Seoul National University, Seoul, 08826, Korea.
Exp Mol Med. 2023 Oct;55(10):2238-2247. doi: 10.1038/s12276-023-01095-w. Epub 2023 Oct 2.
Histone acetylation involves the transfer of two-carbon units to the nucleus that are embedded in low-concentration metabolites. We found that lactate, a high-concentration metabolic byproduct, can be a major carbon source for histone acetylation through oxidation-dependent metabolism. Both in cells and in purified nuclei, C-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%). In the purified nucleus, this process depends on nucleus-localized lactate dehydrogenase (LDHA), knockout (KO) of which abrogates incorporation. Heterologous expression of nucleus-localized LDHA reverses the KO effect. Lactate itself increases histone acetylation, whereas inhibition of LDHA reduces acetylation. In vitro and in vivo settings exhibit different lactate incorporation patterns, suggesting an influence on the microenvironment. Higher nuclear LDHA localization is observed in pancreatic cancer than in normal tissues, showing disease relevance. Overall, lactate and nuclear LDHA can be major structural and regulatory players in the metabolism-epigenetics axis controlled by the cell's own status or the environmental status.
组蛋白乙酰化涉及将嵌入在低浓度代谢物中的两个碳单位转移到细胞核中。我们发现，乳酸作为一种高浓度的代谢副产物，可以通过氧化依赖的代谢成为组蛋白乙酰化的主要碳源。无论是在细胞中还是在纯化的核中，C-乳酸碳都被整合到组蛋白 H4 中（最大整合：~60%）。在纯化的核中，这个过程依赖于位于核内的乳酸脱氢酶（LDHA），LDHA 的敲除（KO）会阻止整合。核定位的 LDHA 的异源表达可逆转 KO 效应。乳酸本身可增加组蛋白乙酰化，而 LDHA 的抑制则降低乙酰化。体外和体内环境表现出不同的乳酸整合模式，提示其对微环境的影响。与正常组织相比，胰腺癌中核 LDHA 的定位更高，表明与疾病相关。总的来说，乳酸和核内的 LDHA 可以成为由细胞自身状态或环境状态控制的代谢-表观遗传学轴的主要结构和调节因子。
