title: Curcumin up-regulates phosphatase and tensin homologue deleted on chromosome 10 through microRNA-mediated control of DNA methylation--a novel mechanism suppressing liver fibrosis.
abstract: Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) has been reported to play a role in the suppression of activated hepatic stellate cells (HSCs). Moreover, it has been demonstrated that hypermethylation of the PTEN promoter is responsible for the loss of PTEN expression during HSC activation. Methylation is now established as a fundamental regulator of gene transcription. MicroRNAs (miRNAs), which can control gene expression by binding to their target genes for degradation and/or translational repression, were found to be involved in liver fibrosis. However, the mechanism responsible for miRNA-mediated epigenetic regulation in liver fibrosis still remained unclear. In the present study, curcumin treatment significantly resulted in the inhibition of cell proliferation and an increase in the apoptosis rate through the up-regulation of PTEN associated with a decreased DNA methylation level. Only DNA methyltransferase 3b (DNMT3b) was reduced in vivo and in vitro after curcumin treatment. Further studies were performed aiming to confirm that the knockdown of DNMT3b enhanced the loss of PTEN methylation by curcumin. In addition, miR-29b was involved in the hypomethylation of PTEN by curcumin. MiR-29b not only was increased by curcumin in activated HSCs, but also was confirmed to target DNMT3b by luciferase activity assays. Curcumin-mediated PTEN up-regulation, DNMT3b down-regulation and PTEN hypomethylation were all attenuated by miR-29b inhibitor. Collectively, it is demonstrated that curcumin can up-regulate miR-29b expression, resulting in DNMT3b down-regulation in HSCs and epigenetically-regulated PTEN involved in the suppression of activated HSCs. These results indicate that miRNA-mediated epigenetic regulation may be a novel mechanism suppressing liver fibrosis.
authors.affiliation: Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, China.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Zheng
authors.forename: Cunzao
authors.initials: C
authors.lastname: Wu
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Lin
authors.forename: Yong
authors.initials: Y
authors.lastname: Guo
authors.forename: Liang
authors.initials: L
authors.lastname: Shi
authors.forename: Peihong
authors.initials: P
authors.lastname: Dong
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Lu
authors.forename: Shenmeng
authors.initials: S
authors.lastname: Gao
authors.forename: Yi
authors.initials: Y
authors.lastname: Liao
authors.forename: Bicheng
authors.initials: B
authors.lastname: Chen
authors.forename: Fujun
authors.initials: F
authors.lastname: Yu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002872:Chromosome Deletion; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D003474:Curcumin / Q000494:pharmacology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects*; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097584:DNA Methyltransferase 3B
chemical_list: D000970:Antineoplastic Agents; D002251:Carbon Tetrachloride; D003474:Curcumin; D004248:DNA (Cytosine-5-)-Methyltransferases; D008156:Luciferases; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000097584:DNA Methyltransferase 3B; C532045:MIRN29a microRNA, human; C487216:Pten protein, rat
keywords: DNA methylation; DNA methyltransferase; hepatic stellate cells; microRNA-29b; phosphatase and tensin homologue deleted on chromosome 10