Identification of hypoxia-inducible factor-1alpha (HIF-1alpha) polymorphism as a mutation in prostate cancer that prevents normoxia-induced degradation.
BACKGROUND
Hypoxia-inducible factor-1alpha (HIF-1alpha) regulates cellular responses to hypoxia and is rapidly degraded under normoxia through von Hippel-Lindau (VHL) mediated ubiquitination. Although HIF-1alpha stabilization appears to be the molecular basis for VHL-associated cancers, stabilizing mutations in HIF-1alpha have not been reported.


METHODS
A series of 15 metastatic androgen independent prostate cancers were examined for mutations in the oxygen-dependent domain (ODD) of HIF-1alpha by PCR amplification and DNA sequencing.


RESULTS
A somatic proline to serine mutation in codon 582 (P582S) was identified in one sample. Transfection studies with a HIF-1alpha regulated reporter gene showed increased transcriptional activity that correlated with higher mutant HIF-1alpha protein expression. Increased expression of the P582S mutant induced by iron chelation, which blocks proline hydroxylation of wild-type HIF-1alpha, was markedly attenuated. The mutant also showed increased stability under normoxic versus hypoxic conditions.


CONCLUSIONS
The P582S HIF-1alpha is a stable variant and HIF-1alpha mutation is a mechanism for enhancing HIF-1alpha activity in human cancer. The recent identification of the identical P582S HIF-1alpha as a polymorphism suggests that this variant may increase tumor susceptibility or cause more aggressive biological behavior.
Fu
Xinyu S
XS
Cancer Biology Program, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Choi
Eunis
E
Bubley
Glenn J
GJ
Balk
Steven P
SP
D001706:Biopsy; D001853:Bone Marrow / Q000473:pathology; D002460:Cell Line; D004273:DNA, Neoplasm / Q000032:analysis / Q000737:chemistry / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008156:Luciferases / Q000235:genetics; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010100:Oxygen / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000235:genetics*; D011993:Recombinant Fusion Proteins; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D004273:DNA, Neoplasm; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D006899:Mixed Function Oxygenases; D008156:Luciferases; D010100:Oxygen