HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression.
Hypoxia promotes genetic instability by undefined mechanisms. The transcription factor HIF-1alpha is crucial for the cellular response to hypoxia and is frequently overexpressed in human cancers, resulting in the activation of genes essential for cell survival. Here, we demonstrate that HIF-1alpha is responsible for genetic instability at the nucleotide level by inhibiting MSH2 and MSH6, thereby decreasing levels of the MSH2-MSH6 complex, MutSalpha, which recognizes base mismatches. HIF-1alpha displaces the transcriptional activator Myc from Sp1 binding to repress MutSalpha expression in a p53-dependent manner; Sp1 serves as a molecular switch by recruiting HIF-1alpha to the gene promoter under hypoxia. Furthermore, in human sporadic colon cancers, HIF-1alpha overexpression is statistically associated with the loss of MSH2 expression, especially when p53 is immunochemically undetectable. These findings indicate that the regulation of DNA repair is an integral part of the hypoxic response, providing molecular insights into the mechanisms underlying hypoxia-induced genetic instability.
Koshiji
Minori
M
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
To
Kenneth K-W
KK
Hammer
Stefanie
S
Kumamoto
Kensuke
K
Harris
Adrian L
AL
Modrich
Paul
P
Huang
L Eric
LE
D015687:Cell Hypoxia; D043171:Chromosomal Instability; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051718:MutS Homolog 2 Protein; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C489427:MYC protein, human; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein