Epigenetic loss of CDH1 correlates with multidrug resistance in human hepatocellular carcinoma cells.
Promoter CpG hypermethylation of tumor suppressor genes is an essential step in cancer progression but little is known about its effect on cancer multidrug resistance. In this study, we showed that CDH1 promoter was hypermethylated in drug resistance of a doxorubicin-induced multidrug resistant hepatocellular carcinoma cell line R-HepG2. Transfection of CDH1 cDNA into R-HepG2 cells led to increased amount of doxorubicin uptake, decreased cell viability, decreased P-glycoprotein expression and increased apoptotic population of cells exposed to doxorubicin. Proto-oncogene tyrosine-protein kinase FYN was over-expressed in R-HepG2 cells which displayed a negative correlation with the expression of CDH1. FYN was knocked down in R-HepG2 cells, leading to less drug resistance by increased cell viability, increased doxorubicin uptake and attenuated P-glycoprotein expression. Our findings identified epigenetic silencing of CDH1 in cancer cells might be a new molecular event of multidrug resistance.
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region. heinzwg@163.com
Lei
L
Jiang
Judy Yuet-Wa
JY
Chan
Kwok-Pui
KP
Fung
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015703:Antigens, CD; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015820:Cadherins / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D019175:DNA Methylation; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D057890:Epigenomics; D016147:Genes, Tumor Suppressor; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D004317:Doxorubicin