Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors.
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.
Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Mengtao
M
Xiao
Hui
H
Yang
Wei
W
Xu
Shenghong
S
Ma
Huaipeng
H
Lin
Honguang
H
Zhu
Lixia
L
Liu
Ying
Y
Liu
Chen
C
Yang
Yanhui
Y
Xu
Shimin
S
Zhao
Dan
D
Ye
Yue
Y
Xiong
Kun-Liang
KL
Guan
D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects; D049308:Dioxygenases / Q000378:metabolism; D043169:Endostatins / Q000378:metabolism; D005649:Fumarate Hydratase / Q000235:genetics*; D005650:Fumarates / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D015894:Genome, Human / Q000235:genetics; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics*; D019802:Succinic Acid / Q000737:chemistry / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000235:genetics
D043169:Endostatins; D005650:Fumarates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D025521:Tumor Suppressor Proteins; D019802:Succinic Acid; D049308:Dioxygenases; D056466:Histone Demethylases; D013385:Succinate Dehydrogenase; D005649:Fumarate Hydratase