DNA methyltransferase 3A promotes cell proliferation by silencing CDK inhibitor p18INK4C in gastric carcinogenesis

被引：22

作者：

Cui, He ^{[1
]}

Zhao, Chengcheng ^{[1
]}

Gong, Pihai ^{[1
]}

Wang, Ling ^{[1
]}

Wu, Huazhang ^{[1
]}

Zhang, Kun ^{[2
]}

Zhou, Rongping ^{[3
]}

Wang, Li ^{[4
]}

Zhang, Ting ^{[4
]}

Zhong, Sheng ^{[4
]}

Fan, Hong ^{[1
]}

机构：

[1] Southeast Univ, Key Lab Dev Genes & Human Dis, Minist Educ, Dept Med Genet & Dev Biol,Med Sch, Nanjing 210009, Peoples R China

[2] Harbin Med Univ, Affiliated Hosp 3, Canc Hosp, Harbin 150081, Peoples R China

[3] Nanjing Med Univ, Affiliated Jiangning Hosp, Jiangning Hosp, Nanjing 211100, Jiangsu, Peoples R China

[4] Capital Inst Pediat, Beijing Municipal Key Lab Child Dev & Nutr, Beijing 100020, Peoples R China

来源：

SCIENTIFIC REPORTS | 2015年 / 5卷

基金：

中国国家自然科学基金;

关键词：

CLINICAL-SIGNIFICANCE; TUMOR-SUPPRESSOR; CANCER; EXPRESSION; METHYLATION; GENE; HYPERMETHYLATION; PROTEINS; P16; INACTIVATION;

D O I：

10.1038/srep13781

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Little is known about the roles of DNA methyltransferase 3A (DNMT3A) in gastric carcinogenesis. Here, we reported that the exogenous expression of DNMT3A promoted gastric cancer (GC) cell proliferation by accelerating the G1/S transition. Subsequently, p18(INK4C) was identified as a downstream target of DNMT3A. The elevated expression of DNMT3A suppressed p18(INK4C) at least at the transcriptional level. Depletion of p18(INK4C) expression in GC cells induced cell cycle progression, whereas its re-expression alleviated the effect of DNMT3A overexpression on G1/S transition. Furthermore, we found that DNMT3A modulated p18(INK4C) by directly binding to and silencing the p18(INK4C) gene via promoter hypermethylation. In clinical GC tissue specimens analyzed, the level of methylation of p18(INK4C) detected in tumor tissues was significantly higher than that in paired non-tumor tissues. Moreover, elevated level of DNMT3A expression was associated with the differentiation of GC tissues and was negatively correlated with the p18(INK4C) expression level. Taken together, our results found that DNMT3A contributes to the dysregulation of the cell cycle by repressing p18(INK4C) in a DNA methylation-dependent manner, suggesting that DNMT3A-p18(INK4C) axis involved in GC. These findings provide new insights into gastric carcinogenesis and a potential therapeutic target for GC that may be further investigated in the future.

引用

页数：13

共 45 条

[1]

[Anonymous], CA CANC J CLIN, DOI DOI 10.3322/CAAC.20107

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