Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Genes Dev. 2012 Jun 15;26(12):1326-38. doi: 10.1101/gad.191056.112. Epub 2012 Jun 7.
Two Krebs cycle genes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are mutated in a subset of human cancers, leading to accumulation of their substrates, fumarate and succinate, respectively. Here we demonstrate that fumarate and succinate are competitive inhibitors of multiple α-ketoglutarate (α-KG)-dependent dioxygenases, including histone demethylases, prolyl hydroxylases, collagen prolyl-4-hydroxylases, and the TET (ten-eleven translocation) family of 5-methlycytosine (5mC) hydroxylases. Knockdown of FH and SDH results in elevated intracellular levels of fumarate and succinate, respectively, which act as competitors of α-KG to broadly inhibit the activity of α-KG-dependent dioxygenases. In addition, ectopic expression of tumor-derived FH and SDH mutants inhibits histone demethylation and hydroxylation of 5mC. Our study suggests that tumor-derived FH and SDH mutations accumulate fumarate and succinate, leading to enzymatic inhibition of multiple α-KG-dependent dioxygenases and consequent alterations of genome-wide histone and DNA methylation. These epigenetic alterations associated with mutations of FH and SDH likely contribute to tumorigenesis.
两个克雷布斯循环基因，延胡索酸水合酶（FH）和琥珀酸脱氢酶（SDH），在人类癌症的一个亚群中发生突变，导致它们的底物延胡索酸和琥珀酸分别积累。在这里，我们证明了延胡索酸和琥珀酸分别是多种α-酮戊二酸（α-KG）依赖性加双氧酶的竞争性抑制剂，包括组蛋白去甲基酶、脯氨酰羟化酶、胶原蛋白脯氨酰-4-羟化酶和 TET（十-十一易位）家族的 5-甲基胞嘧啶（5mC）羟化酶。FH 和 SDH 的敲低分别导致细胞内延胡索酸和琥珀酸水平升高，它们作为 α-KG 的竞争物广泛抑制 α-KG 依赖性加双氧酶的活性。此外，肿瘤衍生的 FH 和 SDH 突变体的异位表达抑制组蛋白去甲基化和 5mC 的羟化。我们的研究表明，肿瘤衍生的 FH 和 SDH 突变积累延胡索酸和琥珀酸，导致多种 α-KG 依赖性加双氧酶的酶抑制，并导致全基因组组蛋白和 DNA 甲基化的改变。与 FH 和 SDH 突变相关的这些表观遗传改变可能有助于肿瘤发生。
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