DNA methyltransferase 3A promotes cell proliferation by silencing CDK inhibitor p18INK4C in gastric carcinogenesis.
DNA methyltransferase 3A promotes cell proliferation by silencing CDK inhibitor p18INK4C in gastric carcinogenesis.
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DOI：
10.1038/srep13781
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发表时间：
2015-09-09
影响因子：
4.6
通讯作者：
Fan H
中科院分区：
文献类型：
--
作者：
Cui H;Zhao C;Gong P;Wang L;Wu H;Zhang K;Zhou R;Wang L;Zhang T;Zhong S;Fan H
DNA甲基转移酶3A（DNMT 3A）在胃癌发生中的作用尚不清楚。本研究报道了外源性DNMT 3A基因的表达通过促进胃癌细胞G1/S期转化而促进胃癌细胞增殖。随后，p18 INK 4C被鉴定为DNMT 3A的下游靶标。DNMT 3A的表达升高至少在转录水平上抑制了p18 INK 4C。p18 INK 4C在GC细胞中的表达缺失诱导细胞周期进展，而其重新表达减轻了DNMT 3A过表达对G1/S转换的影响。此外，我们发现DNMT 3A通过启动子超甲基化直接结合并沉默p18 INK 4C基因来调节p18 INK 4C。在分析的临床GC组织标本中，在肿瘤组织中检测到的p18 INK 4C甲基化水平显著高于配对的非肿瘤组织。DNMT 3A表达水平与胃癌组织分化程度相关，与p18 INK 4C表达水平呈负相关。综上所述，我们的研究结果发现，DNMT 3A通过抑制p18 INK 4C以DNA甲基化依赖的方式参与细胞周期的失调，表明DNMT 3A-p18 INK 4C轴参与GC。这些发现为胃癌的发生提供了新的见解，并为将来可能进一步研究的GC提供了潜在的治疗靶点。
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, p18INK4C was identified as a downstream target of DNMT3A. The elevated expression of DNMT3A suppressed p18INK4C at least at the transcriptional level. Depletion of p18INK4C 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 p18INK4C by directly binding to and silencing the p18INK4C gene via promoter hypermethylation. In clinical GC tissue specimens analyzed, the level of methylation of p18INK4C 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 p18INK4C expression level. Taken together, our results found that DNMT3A contributes to the dysregulation of the cell cycle by repressing p18INK4C in a DNA methylation-dependent manner, suggesting that DNMT3A-p18INK4C 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.