Tumor hypoxia causes DNA hypermethylation by reducing TET activity
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE71403 | GEO | 2016/09/01
SECONDARY ACCESSION(S): PRJNA291096
REPOSITORIES: GEO
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Project description:Genome wide DNA methylation profiling of normoxic and hypoxic non-small-cell lung cancer samples for 5mC and 5hmC. The Illumina Infinium 450k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation and hydroxymethylation profiles across 485,512 CpGs from DNA extracted from fresh-frozen tumor samples. Samples included 12 hypoxic and 12 normoxic tumor samples, with hypoxia determined according to the hypoxia metagene score (Buffa et al, Br J Cancer 2010). To profile hydroxymethylation, 5hmC was glycosylated and 5mC was oxidised as described by Yu and colleagues (Nat Protoc 2012), and hydroxymethylation and methylation were differentially profiled according to the Nazor and colleagues (Genomics 2014). Hypermethylation of tumor suppressor gene (TSG) promoters confers growth advantages to cancer cells, but how these changes arise is poorly understood. Here, we report that tumor hypoxia reduces the activity of oxygen-dependent TET enzymes, which catalyze DNA de-methylation through 5-methylcytosine oxidation. This occurs independently of hypoxia-associated alterations in TET gene expression, basal metabolism, HIF activity or nuclear reactive oxygen species, but directly depends on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro, while also in patients, gene promoters are markedly more methylated in hypoxic than normoxic tumors. Affected genes are frequently involved in DNA repair, cell cycle regulation, angiogenesis and metastasis, indicating cellular selection of hypermethylation events. Overall, up to 50% of the tumor-associated hypermethylation is ascribable to hypoxia across various cancer types. Accordingly, spontaneous murine breast tumors become hypermethylated when rendered hypoxic through vessel pruning, whereas vessel normalisation rescues this effect. Tumor hypoxia thus acts as a novel regulator underlying DNA methylation.
2016-09-01 | GSE71398 | GEO
Project description:Hypermethylation of tumor suppressor gene (TSG) promoters confers growth advantages to cancer cells, but how these changes arise is poorly understood. Here, we report that tumor hypoxia reduces the activity of oxygen-dependent TET enzymes, which catalyze DNA de-methylation through 5-methylcytosine oxidation. This occurs independently of hypoxia-associated alterations in TET gene expression, basal metabolism, HIF activity or nuclear reactive oxygen species, but directly depends on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro, while also in patients, gene promoters are markedly more methylated in hypoxic than normoxic tumors. Affected genes are frequently involved in DNA repair, cell cycle regulation, angiogenesis and metastasis, indicating cellular selection of hypermethylation events. Overall, up to 50% of the tumor-associated hypermethylation is ascribable to hypoxia across various cancer types. Accordingly, spontaneous murine breast tumors become hypermethylated when rendered hypoxic through vessel pruning, whereas vessel normalisation rescues this effect. Tumor hypoxia thus acts as a novel regulator underlying DNA methylation.
2016-09-01 | GSE71399 | GEO
Project description:Hypermethylation of tumor suppressor gene (TSG) promoters confers growth advantages to cancer cells, but how these changes arise is poorly understood. Here, we report that tumor hypoxia reduces the activity of oxygen-dependent TET enzymes, which catalyze DNA de-methylation through 5-methylcytosine oxidation. This occurs independently of hypoxia-associated alterations in TET gene expression, basal metabolism, HIF activity or nuclear reactive oxygen species, but directly depends on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro, while also in patients, gene promoters are markedly more methylated in hypoxic than normoxic tumors. Affected genes are frequently involved in DNA repair, cell cycle regulation, angiogenesis and metastasis, indicating cellular selection of hypermethylation events. Overall, up to 50% of the tumor-associated hypermethylation is ascribable to hypoxia across various cancer types. Accordingly, spontaneous murine breast tumors become hypermethylated when rendered hypoxic through vessel pruning, whereas vessel normalisation rescues this effect. Tumor hypoxia thus acts as a novel regulator underlying DNA methylation.
2016-09-01 | GSE71402 | GEO
Project description:Hypermethylation of the promoters of tumour suppressor genes represses transcription of these genes, conferring growth advantages to cancer cells. How these changes arise is poorly understood. Here we show that the activity of oxygen-dependent ten-eleven translocation (TET) enzymes is reduced by tumour hypoxia in human and mouse cells. TET enzymes catalyse DNA demethylation through 5-methylcytosine oxidation. This reduction in activity occurs independently of hypoxia-associated alterations in TET expression, proliferation, metabolism, hypoxia-inducible factor activity or reactive oxygen species, and depends directly on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro. In patients, tumour suppressor gene promoters are markedly more methylated in hypoxic tumour tissue, independent of proliferation, stromal cell infiltration and tumour characteristics. Our data suggest that up to half of hypermethylation events are due to hypoxia, with these events conferring a selective advantage. Accordingly, increased hypoxia in mouse breast tumours increases hypermethylation, while restoration of tumour oxygenation abrogates this effect. Tumour hypoxia therefore acts as a novel regulator of DNA methylation.
| S-EPMC5133388 | biostudies-literature
Project description:Hypermethylation of tumor suppressor gene (TSG) promoters confers growth advantages to cancer cells, but how these changes arise is poorly understood. Here, we report that tumor hypoxia reduces the activity of oxygen-dependent TET enzymes, which catalyze DNA de-methylation through 5-methylcytosine oxidation. This occurs independently of hypoxia-associated alterations in TET gene expression, basal metabolism, HIF activity or nuclear reactive oxygen species, but directly depends on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro, while also in patients, gene promoters are markedly more methylated in hypoxic than normoxic tumors. Affected genes are frequently involved in DNA repair, cell cycle regulation, angiogenesis and metastasis, indicating cellular selection of hypermethylation events. Overall, up to 50% of the tumor-associated hypermethylation is ascribable to hypoxia across various cancer types. Accordingly, spontaneous murine breast tumors become hypermethylated when rendered hypoxic through vessel pruning, whereas vessel normalisation rescues this effect. Tumor hypoxia thus acts as a novel regulator underlying DNA methylation.
2016-09-01 | GSE71400 | GEO
Project description:Hypermethylation of tumor suppressor gene (TSG) promoters confers growth advantages to cancer cells, but how these changes arise is poorly understood. Here, we report that tumor hypoxia reduces the activity of oxygen-dependent TET enzymes, which catalyze DNA de-methylation through 5-methylcytosine oxidation. This occurs independently of hypoxia-associated alterations in TET gene expression, basal metabolism, HIF activity or nuclear reactive oxygen species, but directly depends on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro, while also in patients, gene promoters are markedly more methylated in hypoxic than normoxic tumors. Affected genes are frequently involved in DNA repair, cell cycle regulation, angiogenesis and metastasis, indicating cellular selection of hypermethylation events. Overall, up to 50% of the tumor-associated hypermethylation is ascribable to hypoxia across various cancer types. Accordingly, spontaneous murine breast tumors become hypermethylated when rendered hypoxic through vessel pruning, whereas vessel normalisation rescues this effect. Tumor hypoxia thus acts as a novel regulator underlying DNA methylation.
2016-09-01 | GSE71401 | GEO
Project description:Hypoxia, a hallmark of most solid tumors, leads to aberrations in epigenetic modifications promoting malignant tumor phenotypes, including metastatic features and stem cell-like characteristics. Aberrant DNA methylation has been considered to play an essential role during tumor progression and tightly associate with tumor malignancy. However, the mechanism by which hypoxia alters DNA methylation to promote tumor malignancy remains poorly understood. Ten-eleven translocation 1-3 (TET1-3) proteins, which catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), play a critical role in the DNA demethylation that controls different biological processes. Here we demonstrate that the expression of TET1 and TET3 is closely associated with tumor hypoxia, tumor malignancy and poor prognosis of patients with breast cancer. Hypoxia results in deregulation of TET1 and TET3, leading to breast tumor initiating cell (BTIC) properties. Mechanically, hypoxia regulates expression of TET1 and TET3 via hypoxia-inducible factor-1a (HIF-1a), thereby resulting in 5hmC genome-wide changes, which in turn leads to the upregulation of TNFa expression and activation of its downstream p38-MAPK pathway. Importantly, signal transduction through the TET-TNFa-p38-MAPK signaling axis is required for the acquisition of BTIC characteristics and chemotherapy resistance, leading to more malignant tumor phenotypes. Inhibition of the hypoxia-TET-TNFα-p38-MAPK signaling pathway results in compromised BTIC properties and tumorigenicity in vitro and in vivo, suggesting a possible therapeutic strategy.
2015-10-05 | GSE60434 | GEO
Project description:To identify novel hypermethylated genes in colorectal cancer (CRC) and to test their potential application in CRC early diagnosis, we performed a genome-wide screening of 57,723 CpG dinucleotides covering 4,010 genes in paired DNA samples extracted from 3 fresh frozen CRC tissues and their matching non-tumor adjacent tissues from a cohort of 3 CRC patients undergoing curative surgery using MIRA-based microarray. We also validated candidate hypermethylated genes screened by MIRA-based microarray in independent CRC samples using combined bisulfite restriction analysis. A total of 297 CpG dinucleotides in CRC covering 211 genes were found to be hypermethylated in CRC tissues. From these 211 candidate methylated genes, seven novel methylated genes were picked up for validation and three genes were confirmed to be methylated in cancer samples but not in non-cancer samples.We also compared the methylation levels of these three novel hypermethylated genes with those of Vimentin and SEPT9, well-known hypermethylated genes in CRC, and found that methylated PHOX2B, FGF12 and GAD2 were better than methylated Vimentin and SEPT9 in differentiating CRC cancer tissue from normal tissue. Significant enrichment analysis of GO terms of the hypermethylated genes showed that a high proportion of hypermethylated genes in tumor tissues are involved in regulation of transcription.
2011-11-14 | GSE33545 | GEO
Project description:Chronic inflammation is deeply involved in various human disorders, such as cancer, neurodegenerative disorders, and metabolic disorders. Induction of epigenetic alterations, especially aberrant DNA methylation, is one of the major mechanisms, but how it is induced is still unclear. Here, we found that expression of TET genes, methylation erasers, was downregulated in inflamed mouse and human tissues, and that this was caused by upregulation of TET-targeting miRNAs such as MIR20A, MIR26B, and MIR29C, likely due to activation of NF-?B signaling downstream of IL-1? and TNF-?. However, TET knockdown induced only mild aberrant methylation. Nitric oxide (NO), produced by NOS2, enhanced enzymatic activity of DNA methyltransferases (DNMTs), methylation writers, and NO exposure induced minimal aberrant methylation. In contrast, a combination of TET knockdown and NO exposure synergistically induced aberrant methylation, involving genomic regions not methylated by either alone. The results showed that a vicious combination of TET repression, due to NF-?B activation, and DNMT activation, due to NO production, is responsible for aberrant methylation induction in human tissues.
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Project description:Isocitrate dehydrogenases 1 and 2 (IDH1/2) are recurrently mutated in acute myeloid leukemia (AML), but their mechanistic role in leukemogenesis is poorly understood. The inhibition of TET enzymes by D-2-hydroxyglutarate (D-2-HG), which is produced by mutant IDH1/2 (mIDH1/2), has been suggested to promote epigenetic deregulation during tumorigenesis. In addition, mIDH also induces a differentiation block in various cell culture and mouse models. Here we analyze the genomic methylation patterns of AML patients with mIDH using Infinium 450K data from a large AML cohort and found that mIDH is associated with pronounced DNA hypermethylation at tens of thousands of CpGs. Interestingly, however, myeloid leukemia cells overexpressing mIDH, cells that were cultured in the presence of D-2-HG or TET2 mutant AML patients did not show similar methylation changes. In further analyses, we also characterized the methylation landscapes of myeloid progenitor cells and analyzed their relationship to mIDH-associated hypermethylation. Our findings identify the differentiation state of myeloid cells, rather than inhibition of TET-mediated DNA demethylation, as a major factor of mIDH-associated hypermethylation in AML. Furthermore, our results are also important for understanding the mode of action of currently developed mIDH inhibitors.
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