Open AccessDNA methylation of interferon regulatory factors in gastric cancer and noncancerous gastric mucosae
Author(s) -
Yamashita Masaki,
Toyota Minoru,
Suzuki Hiromu,
Nojima Masanori,
Yamamoto Eiichiro,
Kamimae Seiko,
Watanabe Yoshiyuki,
Kai Masahiro,
Akashi Hirofumi,
Maruyama Reo,
Sasaki Yasushi,
Yamano Hiroo,
Sugai Tamotsu,
Shinomura Yasuhisa,
Imai Kohzoh,
Tokino Takashi,
Itoh Fumio
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2010.01581.x
Subject(s) - cancer research , dna methylation , irf8 , cancer , carcinogenesis , biology , interferon regulatory factors , epigenetics , demethylating agent , cancer cell , irf4 , gene silencing , interferon , immunology , transcription factor , gene expression , immune system , innate immune system , gene , genetics
Interferon regulatory factors (IRFs) are transcription factors known to play key roles in innate and adaptive immune responses, cell growth, apoptosis, and development. Their function in tumorigenesis of gastric cancer remains to be determined, however. In the present study, therefore, we examined epigenetic inactivation of IRF1–9 in a panel of gastric cancer cell lines. We found that expression of IRF4 , IRF5 , and IRF8 was frequently suppressed in gastric cancer cell lines; that methylation of the three genes correlated with their silencing; and that treating the cells with the demethylating agent 5‐aza‐2′‐deoxycytidine (DAC) restored their expression. Expression of IRF5 in cancer cells was enhanced by the combination of DAC treatment and adenoviral vector‐mediated expression of p53, p63, or p73. Interferon‐γ‐induced expression of IRF8 was also enhanced by DAC. Moreover, treating gastric cancer cells with DAC enhanced the suppressive effects of interferon‐α, interferon‐β, and interferon‐γ on cell growth. Among a cohort of 455 gastric cancer and noncancerous gastric tissue samples, methylation of IRF4 was frequently observed in both gastric cancer specimens and noncancerous specimens of gastric mucosa from patients with multiple gastric cancers, which suggests IRF4 methylation could be a useful molecular marker for diagnosing recurrence of gastric cancers. Our findings indicate that epigenetic IRF inactivation plays a key role in tumorigenesis of gastric cancer, and that inhibition of DNA methylation may restore the antitumor activity of interferons through up‐regulation of IRFs . ( Cancer Sci 2010)