title: HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability.
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.
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Isaacs
authors.forename: Yun Jin
authors.initials: YJ
authors.lastname: Jung
authors.forename: David R
authors.initials: DR
authors.lastname: Mole
authors.forename: Sunmin
authors.initials: S
authors.lastname: Lee
authors.forename: Carlos
authors.initials: C
authors.lastname: Torres-Cabala
authors.forename: Yuen-Li
authors.initials: YL
authors.lastname: Chung
authors.forename: Maria
authors.initials: M
authors.lastname: Merino
authors.forename: Jane
authors.initials: J
authors.lastname: Trepel
authors.forename: Berton
authors.initials: B
authors.lastname: Zbar
authors.forename: Jorge
authors.initials: J
authors.lastname: Toro
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
mesh_terms: D000328:Adult; D000483:Alleles; D051792:Basic Helix-Loop-Helix Proteins; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005649:Fumarate Hydratase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005650:Fumarates / Q000378:metabolism* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D018231:Leiomyomatosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors; D013577:Syndrome; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D005649:Fumarate Hydratase; D005650:Fumarates; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D009687:Nuclear Proteins; D011393:Procollagen-Proline Dioxygenase; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C032005:fumaric acid