| Literature DB >> 22677546 |
Mengtao Xiao1, Hui Yang, Wei Xu, Shenghong Ma, Huaipeng Lin, Honguang Zhu, Lixia Liu, Ying Liu, Chen Yang, Yanhui Xu, Shimin Zhao, Dan Ye, Yue Xiong, Kun-Liang Guan.
Abstract
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.Entities:
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Year: 2012 PMID： 22677546 PMCID： PMC3387660 DOI： 10.1101/gad.191056.112
Source DB: PubMed Journal: Genes Dev ISSN： 0890-9369 Impact factor: 12.890