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Epigenetic Alteration by DNA Promoter Hypermethylation of Genes Related to Transforming Growth Factor-β (TGF-β) Signaling in Cancer
Kobe University Graduate School of Medicine, Division of Diagnostic Molecular Pathology, Kobe 650-0017, Japan
Pathology Research Unit, Department of Medical Research (Central Myanmar), Naypyitaw, Union of Myanmar
Ehime University Graduate School of Medicine, Toon 791-0295, Ehime, Japan
* Author to whom correspondence should be addressed.
Received: 15 December 2010; in revised form: 22 February 2011 / Accepted: 24 February 2011 / Published: 3 March 2011
Abstract: Epigenetic alterations in cancer, especially DNA methylation and histone modification, exert a significant effect on the deregulated expression of cancer-related genes and lay an epigenetic pathway to carcinogenesis and tumor progression. Global hypomethylation and local hypermethylation of CpG islands in the promoter region, which result in silencing tumor suppressor genes, constitute general and major epigenetic modification, the hallmark of the neoplastic epigenome. Additionally, methylation-induced gene silencing commonly affects a number of genes and increases with cancer progression. Indeed, cancers with a high degree of methylation (CpG island methylator phenotype/CIMP) do exist and represent a distinct subset of certain cancers including colorectal, bladder and kidney. On the other hand, signals from the microenvironment, especially those from transforming growth factor-β (TGF-β), induce targeted de novo epigenetic alterations of cancer-related genes. While TGF-β signaling has been implicated in two opposite roles in cancer, namely tumor suppression and tumor promotion, its deregulation is also partly induced by epigenetic alteration itself. Although the epigenetic pathway to carcinogenesis and cancer progression has such reciprocal complexity, the important issue is to identify genes or signaling pathways that are commonly silenced in various cancers in order to find early diagnostic and therapeutic targets. In this review, we focus on the epigenetic alteration by DNA methylation and its role in molecular modulations of the TGF-β signaling pathway that cause or underlie altered cancer-related gene expression in both phases of early carcinogenesis and late cancer progression.
Keywords: methylation; TGF-β signaling; cancer
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Khin, S.S.; Kitazawa, R.; Kondo, T.; Idei, Y.; Fujimoto, M.; Haraguchi, R.; Mori, K.; Kitazawa, S. Epigenetic Alteration by DNA Promoter Hypermethylation of Genes Related to Transforming Growth Factor-β (TGF-β) Signaling in Cancer. Cancers 2011, 3, 982-993.
Khin SS, Kitazawa R, Kondo T, Idei Y, Fujimoto M, Haraguchi R, Mori K, Kitazawa S. Epigenetic Alteration by DNA Promoter Hypermethylation of Genes Related to Transforming Growth Factor-β (TGF-β) Signaling in Cancer. Cancers. 2011; 3(1):982-993.
Khin, Sann Sanda; Kitazawa, Riko; Kondo, Takeshi; Idei, Yuka; Fujimoto, Masayo; Haraguchi, Ryuma; Mori, Kiyoshi; Kitazawa, Sohei. 2011. "Epigenetic Alteration by DNA Promoter Hypermethylation of Genes Related to Transforming Growth Factor-β (TGF-β) Signaling in Cancer." Cancers 3, no. 1: 982-993.