A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing

Ohm, Joyce E.; McGarvey, Kelly M.; Yu, Xiaobing; Cheng, Linzhao; Schuebel, Kornel E.; Cope, Leslie; Mohammad, Helai P.; Chen, Wei; Daniel, Vincent C.; Yu, Wayne; Berman, David M.; Jenuwein, Thomas; Pruitt, Kevin; Sharkis, Saul J.; Watkins, D. Neil; Herman, James G.; Baylin, Stephen B.

doi:10.1038/ng1972

Cited by 980 publications

(892 citation statements)

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“…This is consistent with the notion that cell differentiation is accompanied by epigenetic changes that are responsible for guiding the future phenotypic profile of the progeny (Gan et al, 2007). This phenomenon is not unique to normal stem cells but also may be present aberrantly in cancer stem cells, perhaps having initiated carcinogenesis (Balch et al, 2007;Ohm et al, 2007). Methylation of the CD133 promoter may be generally representative of epigenetic repression of other pluripotency-associated genes (Ruau et al, 2008).…”

Section: Resultssupporting

confidence: 84%

Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells

et al. 2008

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The cancer stem cell hypothesis posits that malignant growth arises from a rare population of progenitor cells within a tumor that provide it with unlimited regenerative capacity. Such cells also possess increased resistance to chemotherapeutic agents. Resurgence of chemoresistant disease after primary therapy typifies epithelial ovarian cancer and may be attributable to residual cancer stem cells, or cancer-initiating cells, that survive initial treatment. As the cell surface marker CD133 identifies cancerinitiating cells in a number of other malignancies, we sought to determine the potential role of CD133 þ cells in epithelial ovarian cancer. We detected CD133 on ovarian cancer cell lines, in primary cancers and on purified epithelial cells from ascitic fluid of ovarian cancer patients. We found CD133 þ ovarian cancer cells generate both CD133 þ and CD133À daughter cells, whereas CD133À cells divide symmetrically. CD133 þ cells exhibit enhanced resistance to platinum-based therapy, drugs commonly used as first-line agents for the treatment of ovarian cancer. Sorted CD133 þ ovarian cancer cells also form more aggressive tumor xenografts at a lower inoculum than their CD133À progeny. Epigenetic changes may be integral to the behavior of cancer progenitor cells and their progeny. In this regard, we found that CD133 transcription is controlled by both histone modifications and promoter methylation. Sorted CD133À ovarian cancer cells treated with DNA methyltransferase and histone deacetylase inhibitors show a synergistic increase in cell surface CD133 expression. Moreover, DNA methylation at the ovarian tissue active P2 promoter is inversely correlated with CD133 transcription. We also found that promoter methylation increases in CD133À progeny of CD133 þ cells, with CD133 þ cells retaining a less methylated or unmethylated state. Taken together, our results show that CD133 expression in ovarian cancer is directly regulated by epigenetic modifications and support the idea that CD133demarcates an ovarian cancer-initiating cell population. The activity of these cells may be epigenetically detected and such cells might serve as pertinent chemotherapeutic targets for reducing disease recurrence.

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Section: Resultssupporting

confidence: 84%

Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells

et al. 2008

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“…Interestingly, Chen and colleagues (Chen et al., 2016) have recently demonstrated that normal tissue signatures are better predictors of DNA hypermethylation changes than ESC signatures. Furthermore, hypermethylation changes were also associated with the repressive histone mark H3K9me3 (Ohm et al., 2007), which was correlated to ZNF genes and DNA repeats in our chromatin state analyses, and which might have a potential relationship with the malignant transformation process (Severson, Tokar, Vrba, Waalkes & Futscher, 2013). …”

Section: Discussionmentioning

confidence: 73%

“…Chromatin state analysis revealed that the hypermethylation‐associated H3K27me3 and H3K4me1/3 marks configured bivalent chromatin domains, as has been extensively described in embryonic stem cells (Fernández et al., 2015; Ohm et al., 2007; Rakyan et al., 2010; Schlesinger et al., 2007; Teschendorff et al., 2010; Widschwendter et al., 2007). Moreover, our data reveal that this chromatin signature is not restricted to only embryonic stem cells, but rather this trend should be considered an extended, global tissue‐independent chromatin signature of DNA hypermethylation in aging and cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Recent research has established polycomb‐target gene promoter hypermethylation as a common epigenetic characteristic of cancer (Schlesinger et al., 2007; Widschwendter et al., 2007). In this scenario, prior to alteration these promoters display an embryonic stem cell “bivalent chromatin pattern” consisting of the repressive histone mark H3K27me3 and the active mark H3K4me3 (Ohm et al., 2007). Genes affected by this process are associated with developmental regulation (Easwaran et al., 2012), implying a possible stem cell origin of cancer whereby aberrant hypermethylation could promote a continuously self‐renewing embryonic‐like state in cancer cells (Teschendorff et al., 2010).…”

Section: Introductionmentioning

confidence: 99%

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Distinct chromatin signatures of DNA hypomethylation in aging and cancer

et al. 2018

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SummaryCancer is an aging‐associated disease, but the underlying molecular links between these processes are still largely unknown. Gene promoters that become hypermethylated in aging and cancer share a common chromatin signature in ES cells. In addition, there is also global DNA hypomethylation in both processes. However, the similarity of the regions where this loss of DNA methylation occurs is currently not well characterized, and it is unknown if such regions also share a common chromatin signature in aging and cancer. To address this issue, we analyzed TCGA DNA methylation data from a total of 2,311 samples, including control and cancer cases from patients with breast, kidney, thyroid, skin, brain, and lung tumors and healthy blood, and integrated the results with histone, chromatin state, and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects. We identified 98,857 CpG sites differentially methylated in aging and 286,746 in cancer. Hyper‐ and hypomethylated changes in both processes each had a similar genomic distribution across tissues and displayed tissue‐independent alterations. The identified hypermethylated regions in aging and cancer shared a similar bivalent chromatin signature. In contrast, hypomethylated DNA sequences occurred in very different chromatin contexts. DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging, while in cancer, loss of DNA methylation was primarily associated with the repressive H3K9me3 mark. Our results suggest that the role of DNA methylation as a molecular link between aging and cancer is more complex than previously thought.

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“…Indeed, several authors reported that PRC2 target genes are enriched among the genes found hypermethylated in cancer. 13,21,46,47 In contrast, genes found hypermethylated also in cirrhosis were depleted for PRC2 target genes in embryonic stem cells. As the PRC2 complex plays an important role in maintaining the stem cell status in undifferentiated cells, hypermethylation of PRC2 targets in HCC supports the hypothesis, that aberrant DNA methylation might occur already in a cancer precursor cell, and the epigenetic changes found in tumor samples might represent a kind of ''stemness memory'' or early stages of tumorigenesis.…”

Section: Discussionmentioning

confidence: 97%

Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma

Ammerpohl

Pratschke

Schafmayer

et al. 2011

Intl Journal of Cancer

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Abberrant DNA methylation is one of the hallmarks of cancerogenesis. Our study aims to delineate differential DNA methylation in cirrhosis and hepatic cancerogenesis. Patterns of methylation of 27,578 individual CpG loci in 12 hepatocellular carcinomas (HCCs), 15 cirrhotic controls and 12 normal liver samples were investigated using an array-based technology. A supervised principal component analysis (PCA) revealed 167 hypomethylated loci and 100 hypermethylated loci in cirrhosis and HCC as compared to normal controls. Thus, these loci show a ''cirrhotic'' methylation pattern that is maintained in HCC. In pairwise supervised PCAs between normal liver, cirrhosis and HCC, eight loci were significantly changed in all analyses differentiating the three groups (p < 0.0001). Of these, five loci showed highest methylation levels in HCC and lowest in control tissue (LOC55908, CELSR1, CRMP1, GNRH2, ALOX12 and ANGPTL7), whereas two loci showed the opposite direction of change (SPRR3 and TNFSF15). Genes hypermethylated between normal liver to cirrhosis, which maintain this methylation pattern during the development of HCC, are depleted for CpG islands, high CpG content promoters and polycomb repressive complex 2 (PRC2) targets in embryonic stem cells. In contrast, genes selectively hypermethylated in HCC as compared to nonmalignant samples showed an enrichment of CpG islands, high CpG content promoters and PRC2 target genes (p < 0.0001). Cirrhosis and HCC show distinct patterns of differential methylation with regards to promoter structure, PRC2 targets and CpG islands.Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and globally the third most common cause of cancer mortality. 1,2 Approximately one million new cases are diagnosed globally each year. The highest incidences are observed in sub-Saharan Africa and Eastern Asia, where hepatitis B virus and hepatitis C virus infections are endemic. HCC incidence is rising also due to an increase in incidence of alcoholic cirrhosis and nonalcoholic steatohepatitis. 3,4 As for many other tumors, the development of HCC is a multistep process characterized by the accumulation of genetic and epigenetic alterations leading to the activation of oncogenes and inactivation or loss of tumor suppressor genes. Genomic alterations as part of the somatic evolution of the cancer genome are common in human cancer in general and also in

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A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing

Cited by 980 publications

References 28 publications

Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells

Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma

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