Human mismatch repair gene, MLH1, is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2

Abstract

Tumor hypoxia has been reported to cause a functional loss in DNA mismatch repair (MMR) system as a result of downregulation of MMR genes, although the precise molecular mechanisms remain unclear. In this study, we focused on the downregulation of a key MMR gene, MLH1, and demonstrated that hypoxia-inducible transcription repressors, differentiated embryo chondrocytes (DEC1 and 2), 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 2, 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 2 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 deacethylasemediated mechanism in cancer cells.

Differentiated Embryo Chondrocyte 1 (DEC1) Represses PPARγ2 Gene through Interacting with CCAAT/Enhancer Binding Protein β (C/EBPβ)

“…4B). We analyzed 10 kb around the PPARγ2 transcription start site to identify the type B (CACGTG) E-box site which is a cognitive DNA sequences for DEC1 homodimers (Nakamura et al, 2008;St-Pierre et al, 2002). In silico analyses reveal that PPARγ2 gene did not contain type B E-box sites.…”

MLH1 protects from resistance acquisition by the histone deacetylase inhibitor trichostatin A in colon tumor cells

“…It also seems that the presence of any lesion or genetic alteration that would have been introduced by high concentrations of TSA does not affect the responsiveness to temozolomide and 6-thioguanine, two cytotoxic agents the effect of which depends on functional MMR. 13 There are several attempts at explaining how loss of accumulation of acetylated histones is brought about and how this leads to (undesired) cell survival. One obvious reason is the expression of multidrug resistance efflux transporters that reduces the availability of the drug within the cell, and another obvious reason is the altered expression of HDACs and/or the altered HDAC enzymatic activity.…”

“…Defective MMR confers resistance to these agents (11) and can increase the mutation rate in tumor cells (27). TSA has recently been described to promote expression of the MLH1 gene (12)(13)(14), to be potentially genotoxic due to hyperacetylation of centromers leading to aneuploidy, chromosome missegregation, and DNA strand breaks (19,20), and to slow radiationinduced DNA damage repair process in part by suppressing BRCA1 gene expression (18) Despite its apparent appeal, this view is rather speculative, and a variety of obscurities remain. For instance, despite the putative effect of TSA on MLH1 expression, it is not completely understood, why MLH1 should protect from TSA-mediated but not from SAHAmediated resistance acquisition as previously reported (1,2), in particular considering the close structural relationship between these two pan-HDAC inhibitors.…”

“…Recent studies (12)(13)(14) have shown that MLH1 expression is positively affected by trichostatin A (TSA), one of the first selective HDAC inhibitor identified and often considered 3 as the model HDAC inhibitor (15). Furthermore, microsatellite instable (MSI) and HDAC-2-mutated tumor cells showed absence of histone hyperacetylation in response to TSA (16) and resistance to TSA-induced apoptosis (17).…”

Influence of hypoxia‑related genetic polymorphisms on the prognosis of patients with metastatic gastric cancer treated with EOF

“…MutL homolog 1 (MLH1), a key DNA mismatch repair (MMR) gene, has been revealed to be specifically reduced in tumor cells and stem cells under hypoxia (16,17), which eventually leads to genetic instability, tumor progression and resistance to chemotherapeutic agents including oxaliplatin, 5-FU, and irinotecan (18)(19)(20)(21).…”