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ID 25937
file
creator
Nakamura, Hideaki
Tanimoto, Keiji
Yunokawa, Mayu
Kato, Yukio
Yoshiga, Koji
Poellinger, Lorenz
Nishiyama, Masahiko
subject
MLH1
DEC1
DEC2
hypoxia
HIF-1
NDC
Medical sciences
abstract
Tumor hypoxia has been reported to cause a functional loss in DNA mismatch repair (MMR) system as a result of down-regulation of MMR genes, although the precise molecular mechanisms remain unclear. In this study, we focused on the down-regulation of a key MMR gene, MLH1, and demonstrated that hypoxia-inducible transcription repressors, DEC1 and DEC2, participated in its transcriptional regulation via their bindings to E-box-like motif(s) in MLH1 promoter region. In all cancer cell lines examined, hypoxia increased expression of DEC1 and DEC2, known as hypoxia-inducible genes, but decreased MLH1 expression in an exposure time-dependent manner at both the mRNA and protein levels. Co-transfection reporter assay revealed that DEC1 and, to greater extent, DEC2 as well as hypoxia repressed MLH1 promoter activity. We further found that the action was remarkably inhibited by trichostatin A, and identified a possible DEC-response element in the MLH1 promoter. In vitro electrophoretic gel mobility shift and chromatin immunoprecipitation assays demonstrated that DEC1 or DEC2 directly bounds to the suggested element, and transient transfection assay revealed that overexpression of DEC2 repressed endogenous MLH1 expression in the cells. Hypoxia-induced DEC may impair MMR function through repression of MLH1 expression, possibly via the histone deacethylase (HDAC)-mediated mechanism in cancer cells.
journal title
Oncogene
volume
Volume 27
start page
4200
end page
4209
date of issued
2008
publisher
Nature Publishing Group
issn
0950-9232
ncid
publisher doi
language
eng
nii type
Journal Article
HU type
Journal Articles
DCMI type
text
format
application/pdf
text version
author
rights
Copyright (c) 2008 Nature Publishing Group
relation url
department
Research Institute for Radiation Biology and Medicine
Graduate School of Biomedical Science