Reducing DNA methylation suppresses colon carcinogenesis by inducing tumor cell differentiation

Hatano, Yuichiro; Semi, Katsunori; Hashimoto, K; Lee, Myeong Sup; Hirata, Akihiro; Tomita, Hiroyuki; Kuno, Toshiki; Takamatsu, Manabu; Aoki, Koji; Taketo, Makoto Mark; Kim, Young-Joon; Hara, Akira; Yamada, Yasuhiro

doi:10.1093/carcin/bgv060

Cited by 27 publications

(23 citation statements)

References 47 publications

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“…18-derived chimeric mice similarly developed microadenomas as well as a small number of macroscopic tumors, suggesting that loss of Apc function alone phenocopies the consequences observed in RTC-derived mice. These results also suggest that the genetic aberrations of colon tumor cells are not sufficient for full-blown tumor development, which is consistent with previous findings showing that de novo DNA methylation plays a pivotal role in the transition from pretumoral microadenomas to tumors in the colon of Apc Min mice (18,26). In agreement with this hypothesis, we confirmed that tumor-specific heterogeneous hypermethylation at Nr5a2 (27) was absent in both RTCs and RTC-derived microadenomas but present in the secondary colon tumors that arose in RTC-derived mice (Fig.…”

Section: The Majority Of Colonic Lesions Remain In a Pretumoral Microsupporting

confidence: 92%

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Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior

Hashimoto

Yamada

Semi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The spectrum of genetic mutations differs among cancers in different organs, implying a cellular context-dependent effect for genetic aberrations. However, the extent to which the cellular context affects the consequences of oncogenic mutations remains to be fully elucidated. We reprogrammed colon tumor cells in an Apc Min/+ (adenomatous polyposis coli) mouse model, in which the loss of the Apc gene plays a critical role in tumor development and subsequently, established reprogrammed tumor cells (RTCs) that exhibit pluripotent stem cell (PSC)-like signatures of gene expression. We show that the majority of the genes in RTCs that were affected by Apc mutations did not overlap with the genes affected in the intestine. RTCs lacked pluripotency but exhibited an increased expression of Cdx2 and a differentiation propensity that was biased toward the trophectoderm cell lineage. Genetic rescue of the mutated Apc allele conferred pluripotency on RTCs and enabled their differentiation into various cell types in vivo. The redisruption of Apc in RTC-derived differentiated cells resulted in neoplastic growth that was exclusive to the intestine, but the majority of the intestinal lesions remained as pretumoral microadenomas. These results highlight the significant influence of cellular context on gene regulation, cellular plasticity, and cellular behavior in response to the loss of the Apc function. Our results also imply that the transition from microadenomas to macroscopic tumors is reprogrammable, which underscores the importance of epigenetic regulation on tumor promotion. iPS cell | cancer epigenetics | plasticity | colon cancer | mouse model

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Section: The Majority Of Colonic Lesions Remain In a Pretumoral Microsupporting

confidence: 92%

“…2B and Fig. S3A), whereas it is often down-regulated in tumors of the colon (18,19). A previous study showed that the overexpression of Cdx2 in mouse ESCs is sufficient to generate proper trophoblast stem cells (TSCs), the precursors of the differentiated cells of the placenta (20).…”

Section: Rtcs Lack the Ability To Form Teratomas But Exhibit The Propmentioning

confidence: 96%

Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior

Hashimoto

Yamada

Semi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…[58][59][60] Hatano et al also reported that DNA demethylation exerts a tumor suppressor effect in the colon by inducing tumor cell differentiation. 61 Thus, global DNA methylation regulates gene expression in a highly context-dependent manner. 62 Hypermethylation of tumor suppressor gene/gene family promoters is generally observed in cancers Epigenetic silencing of tumor suppressor genes (TSGs) is often associated with the tumorigenic process.…”

Section: Dna Methylation Dysregulation In Tumor Initiation and Develomentioning

confidence: 99%

Mutual regulation of microRNAs and DNA methylation in human cancers

Wang¹,

Wu²,

Claret

2017

Epigenetics

129

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microRNAs (miRNAs) and DNA methylation are the 2 epigenetic modifications that have emerged in recent years as the most critical players in the regulation of gene expression. Compelling evidence has indicated the roles of miRNAs and DNA methylation in modulating cellular transformation and tumorigenesis. miRNAs act as negative regulators of gene expression and are involved in the regulation of both physiologic conditions and during diseases, such as cancer, inflammatory diseases, and psychiatric disorders, among others. Meanwhile, aberrant DNA methylation manifests in both global genome changes and in localized gene promoter changes, which influences the transcription of cancer genes. In this review, we described the mutual regulation of miRNAs and DNA methylation in human cancers. miRNAs regulate DNA methylation by targeting DNA methyltransferases or methylation-related proteins. On the other hand, both hyper-and hypo-methylation of miRNAs occur frequently in human cancers and represent a new level of complexity in gene regulation. Therefore, understanding the mechanisms underlying the mutual regulation of miRNAs and DNA methylation may provide helpful insights in the development of efficient therapeutic approaches.

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“…Epigenetic changes such as DNA methylation are now recognized as mechanisms which regulate gene expression and ultimately contribute to the malignant phenotype [16–19]. DNA methylation is a reliable epigenetic marker that is crucial for many biological processes including cell differentiation, X-chromosome inactivation, transcription silencing, and genomic imprinting [20–23]. DNA methylation specifically occurs in CpG islands, which is predominantly in or near the promoters of mammalian genes [24].…”

Section: Discussionmentioning

confidence: 99%

Methylation level of CpG islands in GGH gene promoter in pediatric acute leukemia

Liu

Mai

et al. 2017

PLoS ONE

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Backgroundγ-Glutamyl hydrolase (GGH) regulates intracellular folates and antifolates such as methotrexate (MTX) for proper nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. In addition to genetic polymorphism and karyotypic abnormalities, methylation of CpG island 1 (CpG1) in the promoter region is found to modulate GGH activity by reducing GGH mRNA expression in acute lymphoblastic leukemia (ALL) cells. We aim to investigate methylation status of two CpG islands (CpG1 and CpG2) in the GGH promoter region in pediatric patients with ALL and acute myelogenous leukemia (AML).Methods70B-ALL, 29 AML, 10 ITP (idiopathic thrombocytopenic purpura) and 40 healthy children are recruited in the present study. MS-HRM (methylation-sensitive high-resolution melting) and bisulfite sequencing PCR (BSP) are used to detect methylation change and its level in CpG1 and CpG2 in the GGH promoter region. GGH mRNA expression is quantified by real-time PCR. Correlation between CpG island methylation and GGH mRNA expression is assessed by statistical software.ResultsMethylations of CpG1 are detected in leukemia cells samples obtained from 30.9% (21/68) of patients with ALL and 20.7% (6/29) of patients with AML. These methylations are not detected in the controls. Methylations of CpG2 are detected in leukemia cell samples obtained from 44.1% (30/68) of the ALL patients and 37.9% (11/29) of the AML patients. These percentages are significantly higher than that observed in the control cell samples: 6.0% (3/50) (Fisher's exact test, P = 0.000). The abundance of CpG1 methylation in all leukemia cell samples is classified as Grade I (methylation level is less than 10%) and the abundance of CpG2 methylation in leukemia cell samples is classified in separate grades. Our results indicate that methylation of CpG1 or hypermethylation (the methylation level is greater than 10%) of CpG2 could significantly reduce GGH mRNA expression in leukemia cells from the ALL and AML patients (ALL-CpG1: t = 4.632, P = 0.000; ALL-CpG2: t = 3.250, P = 0.006; AML-CpG1: t = -2.254, P = 0.037; AML-CpG2: t = 1.328, P = 0.202).ConclusionEither methylation of CpG1 or hypermethylation of CpG2 in GGH promoter region can significantly reduce GGH mRNA expression in pediatric patients with acute leukemia, which can improve the response to treatment.

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Reducing DNA methylation suppresses colon carcinogenesis by inducing tumor cell differentiation

Cited by 27 publications

References 47 publications

Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior

Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior

Mutual regulation of microRNAs and DNA methylation in human cancers

Methylation level of CpG islands in GGH gene promoter in pediatric acute leukemia

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