Mitochondrial regulation of cancer associated nuclear DNA methylation.
The onset and progression of cancer is associated with the methylation-dependent silencing of specific genes, however, the mechanism and its regulation have not been established. We previously demonstrated that reduction of mitochondrial DNA content induces cancer progression. Here we found that mitochondrial DNA-deficient LNrho0-8 activates the hypermethylation of the nuclear DNA promoters including the promoter CpG islands of the endothelin B receptor, O6-methylguanine-DNA methyltransferase, and E-cadherin. These are unmethylated and the corresponding gene products are expressed in the parental LNCaP containing mitochondrial DNA. The absence of mitochondrial DNA induced DNA methyltransferase 1 expression which was responsible for the methylation patterns observed. Inhibition of DNA methyltransferase eliminated hypermethylation and expressed gene products in LNrho0-8. These studies demonstrate loss or reduction of mitochondrial DNA resulted in the induction of DNA methyltransferase 1, hypermethylation of the promoters of endothelin B receptor, O6-methylguanine-DNA methyltransferase, and E-cadherin, and reduction of the corresponding gene products.
Xie
Cheng-hui
CH
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham slot 516 Little Rock, AR 72205-7199, USA.
Naito
Akihiro
A
Mizumachi
Takatsugu
T
Evans
Teresa T
TT
Douglas
Michael G
MG
Cooney
Craig A
CA
Fan
Chun-Yang
CY
Higuchi
Masahiro
M
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004272:DNA, Mitochondrial / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*
D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm