HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability.
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.
Isaacs
Jennifer S
JS
Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
Jung
Yun Jin
YJ
Mole
David R
DR
Lee
Sunmin
S
Torres-Cabala
Carlos
C
Chung
Yuen-Li
YL
Merino
Maria
M
Trepel
Jane
J
Zbar
Berton
B
Toro
Jorge
J
Ratcliffe
Peter J
PJ
Linehan
W Marston
WM
Neckers
Len
L
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
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