Epigenetic control of programmed cell death: inhibition by 5-azacytidine of 1,25-dihydroxyvitamin D3-induced programmed cell death in C6.9 glioma cells.
In mammalian DNA cytosine methylation occurs specifically at CpG dinucleotide. Although the full array of function of DNA methylation is yet to be elucidated, it is well established that DNA methylation is an important mechanism involved in gene expression, DNA replication and cancer. Rat glioma C6.9 cells undergo programmed cell death (PCD) after treatment with 1,25-dihydroxyvitamin D3 (1,25-D3). Hence, these cells were used to study whether DNA methylation was involved in the control of PCD. We found that 1,25-D3-mediated PCD of C6.9 cells was suppressed by exposure of the cells to the DNA demethylating agents 5-azacytidine (5-AzaC) and 5-aza-2'-deoxycytidine. This effect remains detectable several cell divisions following removal of 5-AzaC and, therefore, involves DNA methylation as an epigenetic regulatory mechanism of PCD. Accordingly, internucleosomal fragmentation, a feature of apoptosis that is detected in 1,25-D3-treated cells, is no longer observable after treatment of these cells with 5-AzaC. However, 5-AzaC does not totally suppress the responsiveness of C6.9 cells to 1,25-D3 since the induction of the c-myc gene remains unaffected. These results suggest that a change in DNA methylation pattern could suppress 1,25-D3-mediated PCD through the expression of previously hypermethylated genes such as proto-oncogenes with death-repressor activity, endogenous virus sequences or even genes inducing change in the differentiated state of these cells.
Canova
C
C
INSERM U 298, CHU Angers, France.
Chevalier
G
G
Remy
S
S
Brachet
P
P
Wion
D
D
D000818:Animals; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D002117:Calcitriol / Q000494:pharmacology*; D053938:DNA Fragmentation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016259:Genes, myc; D005910:Glioma; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; C064769:N-acetylsphingosine; D000077209:Decitabine; D015254:DNA Modification Methylases; D002117:Calcitriol; D001374:Azacitidine; D013110:Sphingosine