Inhibition of α-KG-dependent Histone and DNA Demethylases by Fumarate and Succinate That Are Accumulated in Mutations of FH and SDH Tumor Suppressors

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2012 Jun 9

PMID 22677546

Citations 563

Authors

Mengtao Xiao

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

Affiliations

Soon will be listed here.

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.

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