Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer.
Mitotic checkpoints prevent errors in chromosome segregation that can lead to neoplasia. Therefore, it is notable that gastric cancers often show impaired checkpoint function. In the present study, we examined the functional consequences of epigenetic inactivation of the mitotic checkpoint gene CHFR in gastric cancers. CHFR expression was silenced by DNA methylation of the 5' region of the gene in 20% of the gastric cancer cell lines tested and in 39% of primary gastric cancers; expression could be restored by treatment with 5-aza-2'-deoxycytidine, a methyltransferase inhibitor. In addition, histones H3 and H4 were found to be deacetylated in cell lines showing aberrant methylation, indicating a role for histone deacetylation in the methylation-dependent gene silencing. Cells not expressing CHFR showed impaired checkpoint function, which led to nuclear localization of cyclin B1 after treatment with docetaxel or paclitaxel, two microtubule inhibitors. Apparently, the absence of CHFR is associated with sensitivity of cells to mitotic stress caused by microtubule inhibition, and restoration of CHFR expression by 5-aza-2'-deoxycytidine or adenoviral gene transfer restored the checkpoint. By affecting mitotic checkpoint function, CHFR inactivation likely plays a key role in tumorigenesis in gastric cancer. Moreover, the aberrant methylation of CHFR appears to be a good molecular marker with which to predict the sensitivity of gastric cancers to microtubule inhibitors.
Satoh
Ayumi
A
First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan.
Toyota
Minoru
M
Itoh
Fumio
F
Sasaki
Yasushi
Y
Suzuki
Hiromu
H
Ogi
Kazuhiro
K
Kikuchi
Takefumi
T
Mita
Hiroaki
H
Yamashita
Toshiharu
T
Kojima
Takashi
T
Kusano
Masanobu
M
Fujita
Masahiro
M
Hosokawa
Masao
M
Endo
Takao
T
Tokino
Takashi
T
Imai
Kohzoh
K
D000107:Acetylation; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D000077143:Docetaxel; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology*; D000075223:Poly-ADP-Ribose Binding Proteins; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D043823:Taxoids / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases
D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D006657:Histones; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D043823:Taxoids; D000077143:Docetaxel; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; D017239:Paclitaxel