title: 5-Aza-2<-deoxycytidine induces hepatoma cell apoptosis via enhancing methionine adenosyltransferase 1A expression and inducing S-adenosylmethionine production.
abstract: In hepatocellular cancer (HCC), lack of response to chemotherapy and radiation treatment can be caused by a loss of epigenetic modifications of cancer cells. Methionine adenosyltransferase 1A is inactivated in HCC and may be stimulated by an epigenetic change involving promoter hypermethylation. Therefore, drugs releasing epigenetic repression have been proposed to reverse this process. We studied the effect of the demethylating reagent 5-aza-2<-deoxycitidine (5-Aza-CdR) on MAT1A gene expression, DNA methylation and S-adenosylmethionine (SAMe) production in the HCC cell line Huh7. We found that MAT1A mRNA and protein expression were activated in Huh7 cells with the treatment of 5-Aza-CdR; the status of promoter hypermethylation was reversed. At the same time, MAT2A mRNA and protein expression was significantly reduced in Huh7 cells treated with 5-Aza-CdR, while SAMe production was significantly induced. However, 5-Aza-CdR showed no effects on MAT2A methylation. Furthermore, 5-Aza-CdR inhibited the growth of Huh7 cells and induced apoptosis and through down-regulation of Bcl-2, up-regulation of Bax and caspase-3. Our observations suggest that 5-Aza- CdR exerts its anti-tumor effects in Huh7 cells through an epigenetic change involving increased expression of the methionine adenosyltransferase 1A gene and induction of S-adenosylmethionine production.
authors.affiliation: Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University, Wuhan, China E-mail : lqy@whu. edu.cn, spss2005@126.com.
authors.forename: Wei-Jun
authors.initials: WJ
authors.lastname: Liu
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Ren
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.forename: Guo-Zheng
authors.initials: GZ
authors.lastname: Yu
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Chang-Sheng
authors.initials: CS
authors.lastname: Li
authors.forename: Zhi-Su
authors.initials: ZS
authors.lastname: Liu
authors.forename: Quan-Yan
authors.initials: QY
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008716:Methionine Adenosyltransferase / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012436:S-Adenosylmethionine / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D000077209:Decitabine; D012436:S-Adenosylmethionine; C506577:MAT1A protein, human; D008716:Methionine Adenosyltransferase; D053148:Caspase 3; D001374:Azacitidine