Abstract
Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Alleles
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Basic Helix-Loop-Helix Transcription Factors
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Carcinoma, Renal Cell / enzymology
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / metabolism*
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DNA-Binding Proteins / analysis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Female
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Fumarate Hydratase / antagonists & inhibitors
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Fumarate Hydratase / genetics*
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Fumarate Hydratase / metabolism
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Fumarates / metabolism*
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Fumarates / pharmacology
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Gene Expression Regulation, Neoplastic
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Humans
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Ketoglutaric Acids / pharmacology
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Kidney Neoplasms / enzymology
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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism*
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Leiomyomatosis / enzymology
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Leiomyomatosis / genetics
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Leiomyomatosis / metabolism*
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Male
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Middle Aged
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Nuclear Proteins / analysis
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Procollagen-Proline Dioxygenase / antagonists & inhibitors
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Syndrome
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Transcription Factors / analysis
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Up-Regulation
Substances
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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Fumarates
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HIF1A protein, human
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Ketoglutaric Acids
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Nuclear Proteins
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Transcription Factors
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endothelial PAS domain-containing protein 1
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fumaric acid
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Procollagen-Proline Dioxygenase
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Fumarate Hydratase