title: DNA methylation as a target of epigenetic therapeutics in cancer.
abstract: Epigenetic alterations have been implicated in the development and progression of human cancer. It is noteworthy that epigenetic modifications, in contrast to genetic mutations, are intrinsically reversible. This triggers an impressive interest of researchers in treatment of cancer patients via targeting epigenetic mechanisms, leading to subsequent intensive investigations of epigenetic drugs as a novel therapeutic intervention. DNA methylation, the major form of epigenetic modifications, is catalyzed by the maintenance DNA methyltransferase (DNMT) 1 and/or the de novo methyltransferases DNMT3A and DNMT3B. Aberrant expression of DNMTs and disruption of DNA methylation are closely associated with multiple forms of cancer, although the exact mechanisms underlying this link remain elusive. An array of tumor suppressor genes (TSGs) frequently sustain promoter hypermethylation, which results in epigenetic silencing of these genes and makes cancer cells acquire growth advantages. DNA demethylating agents, re-activating TSGs via inhibiting hypermethylation of their promoter regions, are currently being tested in clinical trials, and several of them are already applied in clinics. DNA demethylating agents, used either alone or in combination with other agents, such as chemotherapeutic drugs and the histone deacetylase inhibitors, have shown to be effective in treatment of cancer, although only in a small set of patients. In this review, we examine and discuss the most recent advances in epigenetic therapy of cancer, with a focus on DNA demethylating agents.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. kli@epigenetic.us
authors.forename: Keqin K
authors.initials: KK
authors.lastname: Li
authors.forename: Fangcheng
authors.initials: F
authors.lastname: Li
authors.forename: Qiushi S
authors.initials: QS
authors.lastname: Li
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.forename: Bilian
authors.initials: B
authors.lastname: Jin
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D015316:Genetic Therapy; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
chemical_list: D000970:Antineoplastic Agents; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human