Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer.
Epigenetic gene inactivation plays a key role in the development of various types of cancer. Using methylated CpG island amplification coupled with representational difference analysis to identify genes inactivated by DNA methylation in gastric cancer, we identified seven DNA fragments corresponding to the 5' CpG islands of the affected genes. One of the clones recovered was identical to the 5' flanking region of DFNA5, a gene previously shown to be associated with deafness and induced by DNA damage. Further analysis revealed that DFNA5 is expressed in normal tissues but is down-regulated in gastric cancer cell lines due to methylation of the region around its transcription start site. Treating gastric cancer cells that lacked DFNA5 expression with a methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the gene's expression. Methylation of DFNA5 was detected in 50% of primary gastric tumors, and was correlated with positivity for Epstein-Barr virus and the absence of metastasis. Moreover, introduction of exogenous DFNA5 into silenced cells suppressed colony formation. Taken together, these data suggest that the silencing of DFNA5 occurs frequently in gastric cancer and may play a key role in development and progression of the disease.
Akino
Kimishige
K
First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan.
Toyota
Minoru
M
Suzuki
Hiromu
H
Imai
Takashi
T
Maruyama
Reo
R
Kusano
Masanobu
M
Nishikawa
Noriko
N
Watanabe
Yoshiyuki
Y
Sasaki
Yasushi
Y
Abe
Tamaki
T
Yamamoto
Eiichiro
E
Tarasawa
Isao
I
Sonoda
Tomoko
T
Mori
Mitsuru
M
Imai
Kohzoh
K
Shinomura
Yasuhisa
Y
Tokino
Takashi
T
D000368:Aged; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D017931:DNA Primers; D044127:Epigenesis, Genetic; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008875:Middle Aged; D011960:Receptors, Estrogen / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics*; D000094524:Gasdermins
D017931:DNA Primers; D011960:Receptors, Estrogen; C111432:GSDME protein, human; D000094524:Gasdermins