Document Detail


DNMT1 and DNMT3b silencing sensitizes human hepatoma cells to TRAIL-mediated apoptosis via up-regulation of TRAIL-R2/DR5 and caspase-8.
MedLine Citation:
PMID:  20398055     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
DNA methylation plays a critical role in chromatin remodeling and gene expression. DNA methyltransferases (DNMTs) are hypothesized to mediate cellular DNA methylation status and gene expression during mammalian development and in malignant diseases. In this study, we examined the role of DNA methyltransferase 1 (DNMT1) and DNMT3b in cell proliferation and survival of hepatocellular carcinoma (HCC) cells. Gene silencing of both DNMT1 and DNMT3b by targeted siRNA knockdown reduces cell proliferation and sensitizes the cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cell death. The proapoptotic protein caspase-8 demonstrated promoter hypermethylation in HCC cells and was up-regulated by knockdown of DNMT1 and DNMT3b both at mRNA and protein levels. In addition, death receptor TRAIL-R2/DR5 (TRAIL receptor 2/death receptor 5) did not exhibit promoter hypermethylation in HCC cells but was also up-regulated by knockdown of DNMT1 and DNMT3b both at mRNA and protein levels. Consistent with this observation, the combined transfection of DNMT1-siRNA plus DNMT3b-siRNA enhanced formation of the TRAIL-death-inducing signaling complex formation in HCC cells. In conclusion, our data suggest that DNA methylation of specific genomic regions maintained by DNMT1 and DNMT3b plays a critical role in survival of HCC cells, and a simultaneous knockdown of both DNMT1 and DNMT3b may be a novel anticancer strategy for the treatment of HCC.
Authors:
Satoshi Kurita; Hajime Higuchi; Yoshimasa Saito; Nobuhiro Nakamoto; Hiromasa Takaishi; Shinichiro Tada; Hidetsugu Saito; Gregory J Gores; Toshifumi Hibi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-13
Journal Detail:
Title:  Cancer science     Volume:  101     ISSN:  1349-7006     ISO Abbreviation:  Cancer Sci.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-08-16     Completed Date:  2010-09-14     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101168776     Medline TA:  Cancer Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  1431-9     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan. kurita.satoshi@mayo.edu
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MeSH Terms
Descriptor/Qualifier:
Apoptosis*
Carcinoma, Hepatocellular / drug therapy*,  pathology
Caspase 8 / genetics*
Cell Line, Tumor
DNA (Cytosine-5-)-Methyltransferase / antagonists & inhibitors,  genetics,  physiology*
DNA Methylation
Drug Resistance, Neoplasm
Gene Silencing
Humans
Liver Neoplasms / drug therapy*,  pathology
Mitochondrial Proteins / metabolism
Promoter Regions, Genetic
RNA, Small Interfering / genetics
Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics*,  physiology
TNF-Related Apoptosis-Inducing Ligand / pharmacology*
Up-Regulation
Chemical
Reg. No./Substance:
0/Mitochondrial Proteins; 0/RNA, Small Interfering; 0/Receptors, TNF-Related Apoptosis-Inducing Ligand; 0/TNF-Related Apoptosis-Inducing Ligand; 0/death-inducing protein, human; EC 2.1.1.37/DNA (Cytosine-5-)-Methyltransferase; EC 2.1.1.37/DNA (cytosine-5-)-methyltransferase 1; EC 2.1.1.37/DNA methyltransferase 3B; EC 3.4.22.-/Caspase 8

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