Epigenetic inactivation of the CHFR gene in cervical cancer contributes to sensitivity to taxanes.
A relationship between inactivation of mitotic checkpoint genes and sensitivity of cancer cells to anticancer agents has been reported. We investigated the effect of epigenetic inactivation by aberrant hypermethylation of the mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger) on the sensitivity of cervical cancer cells to taxanes. Methylation-specific PCR (MSP) of cervical smears showed aberrant methylation of CHFR in 12.3% (2/14) of adenocarcinoma specimens. In contrast, aberrant DNA methylation was not detected in normal cervical cells or squamous cell carcinoma cells. Aberrant methylation of CHFR was also analyzed in 6 human cervical carcinoma-derived cell lines and was observed in SKG-IIIb and HeLa cells. These cell lines showed high sensitivity to taxanes, but became taxane-resistant upon treatment with 5-azacytidine. Furthermore, suppression of CHFR expression in siRNA-transfected SKG-IIIa cells caused increased sensitivity to taxanes. In conclusion, aberrant methylation of the CHFR gene may be useful as a molecular marker for selection of therapy for patients with cervical adenocarcinoma with a poor prognosis, and may also suggest a new therapeutic strategy of targeting CHFR in cervical cancer. To our knowledge, this study is the first to examine epigenetic inactivation by aberrant hypermethylation of CHFR in cervical cancer.
Banno
Kouji
K
Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo 160-8582, Japan. kbanno@sc.itc.keio.ac.jp
Yanokura
Megumi
M
Kawaguchi
Makiko
M
Kuwabara
Yoshiko
Y
Akiyoshi
Jyunko
J
Kobayashi
Yusuke
Y
Iwata
Takashi
T
Hirasawa
Akira
A
Fujii
Takuma
T
Susumu
Nobuyuki
N
Tsukazaki
Kastumi
K
Aoki
Daisuke
D
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004361:Drug Tolerance; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects*; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics*