Global DNA hypomethylation suppresses squamous carcinogenesis in the tongue and esophagus

Baba, Seiji; Yamada, Yasuhiro; Hatano, Yuichiro; Miyazaki, Yasuo; Mori, Hideki; Shibata, Toshiyuki; Hara, Akira

doi:10.1111/j.1349-7006.2009.01171.x

Cited by 43 publications

(42 citation statements)

References 22 publications

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“…Genetic suppression of a maintenance DNA methyltransferase (Dnmt1) also suppressed tumor development in some of these models (22,27,28). However, so far, the efficacy of suppression of aberrant DNA methylation was not evaluated in chronic inflammationassociated cancers, in which aberrant DNA methylation is heavily involved (29,30).…”

Section: Introductionmentioning

confidence: 99%

Prevention of Helicobacter pylori–Induced Gastric Cancers in Gerbils by a DNA Demethylating Agent

Niwa

Toyoda

Tsukamoto

et al. 2013

Cancer Prevention Research

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Suppression of aberrant DNA methylation is a novel approach to cancer prevention, but, so far, the efficacy of the strategy has not been evaluated in cancers associated with chronic inflammation. Gastric cancers induced by Helicobacter pylori infection are known to involve aberrant DNA methylation and associated with severe chronic inflammation in their early stages. Here, we aimed to clarify whether suppression of aberrant DNA methylation can prevent H. pylori-induced gastric cancers using a Mongolian gerbil model. Administration of a DNA demethylating agent, 5-aza-2 0 -deoxycytidine (5-aza-dC), to gerbils (0.125 mg/kg for 50-55 weeks) decreased the incidence of gastric cancers induced by H. pylori infection and N-methyl-N-nitrosourea (MNU) treatment from 55.2% to 23.3% (P < 0.05). In gastric epithelial cells, DNA methylation levels of six CpG islands (HE6, HG2, SB1, SB5, SF12, and SH6) decreased to 46% to 68% (P < 0.05) of gerbils without 5-aza-dC treatment. Also, the global DNA methylation level decreased from 83.0% AE 4.5% to 80.3% AE 4.4% (mean AE SD) by 5-aza-dC treatment (P < 0.05). By 5-aza-dC treatment, Il1b and Nos2 were downregulated (42% and 58% of gerbils without, respectively) but Tnf was upregulated (187%), suggesting that 5-aza-dC treatment induced dysregulation of inflammatory responses.No obvious adverse effect of 5-aza-dC treatment was observed, besides testicular atrophy. These results showed that 5-aza-dC treatment can prevent H. pylori-induced gastric cancers and suggested that removal of induced DNA methylation and/or suppression of DNA methylation induction can become a target for prevention of chronic inflammation-associated cancers. Cancer Prev Res; 6(4); 263-70. Ó2013 AACR.

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Section: Introductionmentioning

confidence: 99%

Prevention of Helicobacter pylori–Induced Gastric Cancers in Gerbils by a DNA Demethylating Agent

Niwa

Toyoda

Tsukamoto

et al. 2013

Cancer Prevention Research

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“…P3761; dosage, 100 mg/kg; Sigma-Aldrich; Merck Millipore, Darmstadt, Germany) 14 days following transplantation of cells. Tumors (50-150 mm 3 ) were excised using a scalpel and surgical forceps. Excised tumor samples were froze in liquid nitrogen and stored in a freezer at -80˚C for subsequent western blotting analysis and methylation-specific polymerase chain reaction (MSP) analyses.…”

Section: Methodsmentioning

confidence: 99%

“…Research in previous decades has demonstrated that the development of human ESCC occurs due to multiple genetic or epigenetic alterations (3). Epigenetic changes, including increased DNA methylation, are considered to be a primary risk factor in human ESCC development (3).…”

Section: Introductionmentioning

confidence: 99%

“…Epigenetic changes, including increased DNA methylation, are considered to be a primary risk factor in human ESCC development (3). Epigenetic changes are an alternative way to inactivate tumor suppressor genes, and have attracted increasing research (3). DNA methyltransferase 1 (DNMT1) is an endogenous and highly expressed protein involved in alteration of DNA methylation patterns following DNA replication, tumor suppressor gene re-expression and DNA damage.…”

Section: Introductionmentioning

confidence: 99%

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Silencing DNA methyltransferase 1 leads to the activation of the esophageal suppressor gene p16 in vitro and in vivo

et al. 2017

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Abstract. Previous studies have demonstrated that DNA methyltransferase 1 (DNMT1) is required for the maintenance of DNA methylation and epigenetic changes that may lead to the development of esophageal squamous cell carcinoma (ESCC). In order to investigate whether the silencing of DNMT1 protects tumor suppressor genes, including p16, and is able to be used as a potential therapy for human ESCC, short hairpin RNA targeting DNMT1 (shRNA-DNMT1) was synthesized and transfected into the human ESCC lines KYSE150 and KYSE410, which were then injected into the backs of nude mice prior to harvesting. Results from the reverse transcription-quantitative polymerase chain reaction (PCR) and western blotting demonstrated that p16 mRNA expression was increased in the shRNA-DNMT1-transfected ESCC cell lines in vitro and in vivo. Consistent with the immunohistochemistry results, p16 was expressed in tumor tissue from nude mice that had been transplanted with the modified human ESCC lines. It was also observed that p16 methylation was inhibited following transfection with shRNA-DNMT1 as detected using methylation-specific PCR analysis. The results of the present study suggest that silencing DNMT1 serves a protective role through the demethylation and subsequent activation of p16 in vitro and in vivo.

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“…Specifically, hypomorphic expression of Dnmt1 can lead to the development of lymphoma (14). Furthermore, crossing Dnmt1 hypomorphic mice with murine tumor models alters tumor progression, resulting in either increased or decreased tumor development, depending on the disease stage and tissue site (1,7,53). For example, reduced expression of Dnmt1 dramatically decreases intestinal polyp formation in Apc Min/ϩ mice, either alone or in combination with 5-aza-2Ј-deoxycytidine treatment (7,27).…”

mentioning

confidence: 99%

Opposing Roles of Dnmt1 in Early- and Late-Stage Murine Prostate Cancer

Kinney

Moser

Pascual

et al. 2010

Molecular and Cellular Biology

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Previous studies have shown that tumor progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model is characterized by global DNA hypomethylation initiated during early-stage disease and locus-specific DNA hypermethylation occurring predominantly in late-stage disease. Here, we utilized Dnmt1 hypomorphic alleles to examine the role of Dnmt1 in normal prostate development and in prostate cancer in TRAMP. Prostate tissue morphology and differentiation status was normal in Dnmt1 hypomorphic mice, despite global DNA hypomethylation. TRAMP; Dnmt1 hypomorphic mice also displayed global DNA hypomethylation, but were characterized by altered tumor phenotype. Specifically, TRAMP; Dnmt1 hypomorphic mice exhibited slightly increased tumor incidence and significantly increased pathological progression at early ages and, conversely, displayed slightly decreased tumor incidence and significantly decreased pathological progression at advanced ages. Remarkably, hypomorphic Dnmt1 expression abrogated local and distant site macrometastases. Thus, Dnmt1 has tumor suppressor activity in early-stage prostate cancer, and oncogenic activity in late stage prostate cancer and metastasis. Consistent with the biological phenotype, epigenomic studies revealed that TRAMP; Dnmt1 hypomorphic mice show dramatically reduced CpG island and promoter DNA hypermethylation in late-stage primary tumors compared to control mice. Taken together, the data reveal a crucial role for Dnmt1 in prostate cancer and suggest that Dnmt1-targeted interventions may have utility specifically for advanced and/or metastatic prostate cancer.Changes in DNA methyltransferase (Dnmt) expression and DNA methylation are observed in human prostate cancer (3, 38, 41). Of particular interest, genes with tumor suppressive function become hypermethylated and silenced, which correlates with the development of specific disease phenotypes (2,3,38). Although an association between prostate cancer and alterations in DNA methylation has been established, in vivo models are required to determine whether these changes functionally contribute to the disease. In this context, studies in which pharmacological inhibitors of Dnmts were shown to inhibit prostate cancer in murine models have proven informative (34, 56). However, it remains unknown whether genetic disruption of epigenetic components, such as Dnmts, also impacts prostate cancer development. This is a critical question since the pharmacological inhibitors of Dnmts have pleiotropic effects, including those unrelated to activation of methylationsilenced genes (21, 23, 31). Moreover, no studies to date have examined whether Dnmts or DNA methylation play roles in normal prostate development; this information is vital to fully understanding the effects that inhibiting DNA methylation may have on prostate cancer.Dnmt1 is a maintenance DNA methyltransferase that propagates preexisting DNA methylation patterns in genomic DNA (44). Dnmt1 also is involved in de novo DNA methylation in cancer cells and interacts with other ...

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Global DNA hypomethylation suppresses squamous carcinogenesis in the tongue and esophagus

Cited by 43 publications

References 22 publications

Prevention of Helicobacter pylori–Induced Gastric Cancers in Gerbils by a DNA Demethylating Agent

Prevention of Helicobacter pylori–Induced Gastric Cancers in Gerbils by a DNA Demethylating Agent

Silencing DNA methyltransferase 1 leads to the activation of the esophageal suppressor gene p16 in vitro and in vivo

Opposing Roles of Dnmt1 in Early- and Late-Stage Murine Prostate Cancer

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