Sensitivity of human prostate cancer cells to chemotherapeutic drugs depends on EndoG expression regulated by promoter methylation.
Analysis of promoter sequences of all known human cytotoxic endonucleases showed that endonuclease G (EndoG) is the only endonuclease that contains a CpG island, a segment of DNA with high G+C content and a site for methylation, in the promoter region. A comparison of three human prostate cancer cell lines showed that EndoG is highly expressed in 22Rv1 and LNCaP cells. In PC3 cells, EndoG was not expressed and the EndoG CpG island was hypermethylated. The expression of EndoG correlated positively with sensitivity to cisplatin and etoposide, and the silencing of EndoG by siRNA decreased the sensitivity of the cells to the chemotherapeutic agents in the two EndoG-expressing cell lines. 5-aza-2'-deoxycytidine caused hypomethylation of the EndoG promoter in PC3 cells, induced EndoG mRNA and protein expression, and made the cells sensitive to both cisplatin and etoposide. The acetylation of histones by trichostatin A, the histone deacetylase inhibitor, induced EndoG expression in 22Rv1 cells, while it had no such effect in PC3 cells. These data are the first indication that EndoG may be regulated by methylation of its gene promoter, and partially by histone acetylation, and that EndoG is essential for prostate cancer cell death in the used models.
Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Xiaoying
X
Wang
Volodymyr
V
Tryndyak
Eugene O
EO
Apostolov
Xiaoyan
X
Yin
Sudhir V
SV
Shah
Igor P
IP
Pogribny
Alexei G
AG
Basnakian
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D018899:CpG Islands; D019175:DNA Methylation; D004706:Endodeoxyribonucleases / Q000235:genetics* / Q000502:physiology; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics
D000970:Antineoplastic Agents; D005047:Etoposide; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D002945:Cisplatin