N6-methyladenosine mediates arsenite-induced human keratinocyte transformation by suppressing p53 activation.
N6-methyladenosine mediates arsenite-induced human keratinocyte transformation by suppressing p53 activation.
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DOI：
10.1016/j.envpol.2019.113908
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发表时间：
2020-01
影响因子：
8.9
通讯作者：
Tianhe Zhao;Donglei Sun;Manyu Zhao;Yanhao Lai;Yuan Liu;Zunzhen Zhang
中科院分区：
文献类型：
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作者：
Tianhe Zhao;Donglei Sun;Manyu Zhao;Yanhao Lai;Yuan Liu;Zunzhen Zhang
N6-甲基腺苷 (m6A) 是最丰富且可逆的 RNA 修饰，在肿瘤发生中发挥着至关重要的作用。然而，m6A 是否可以调节 p53（一种主要的抗肿瘤蛋白）仍知之甚少。在本研究中，我们使用亚砷酸盐转化的角质形成细胞模型（HaCaT-T 细胞系）探讨了 m6A 对 p53 激活的调节作用。我们通过将人角质形成细胞 HaCaT 细胞暴露于 1 μM 亚砷酸盐 5 个月来创建细胞系。我们发现细胞表现出 m6A 水平升高以及甲基转移酶、去甲基酶和 m6A 阅读器的异常表达。此外，细胞表现出p53活性降低，p53磷酸化、乙酰化和反式激活减少，p53出核率较高。敲除 m6A 甲基转移酶 METTL3 显着降低 m6A 水平，恢复 p53 活化并抑制亚砷酸盐转化细胞中的细胞转化表型。此外，使用生物信息学分析和实验方法，我们证明 m6A 通过 YTHDF2 促进 PRDM2 mRNA 的衰变下调 p53 正调节因子 PRDM2 的表达。我们发现 m6A 通过 YTHDF1 刺激 YY1 和 MDM2 mRNA 的翻译来上调负 p53 调节因子 YY1 和 MDM2 的表达。综上所述，我们的研究揭示了 m6A 通过抑制 p53 激活来介导亚砷酸盐诱导的人类角质形成细胞转化的新作用。这项研究通过 RNA 表观遗传学进一步揭示了砷致癌的机制。
N6-methyladenosine (m6A), the most abundant and reversible RNA modification, plays critical a role in tumorigenesis. However, whether m6A can regulate p53, a leading antitumor protein remains poorly understood. In this study, we explored the regulatory role of m6A on p53 activation using an arsenite-transformed keratinocyte model, the HaCaT-T cell line. We created the cell line by exposing human keratinocyte HaCaT cells to 1 μM arsenite for 5 months. We found that the cells exhibited an increased m6A level along with an aberrant expression of the methyltransferases, demethylase, and readers of m6A. Moreover, the cells exhibited decreased p53 activity and reduced p53 phosphorylation, acetylation, and transactivation with a high nucleus export rate of p53. Knockdown of the m6A methyltransferase, METTL3 significantly decreased m6A level, restoring p53 activation and inhibiting cellular transformation phenotypes in the arsenite-transformed cells. Further, using both a bioinformatics analysis and experimental approaches, we demonstrated that m6A downregulated the expression of the positive p53 regulator, PRDM2, through the YTHDF2-promoted decay of PRDM2 mRNAs. We showed that m6A upregulated the expression of the negative p53 regulator, YY1 and MDM2 through YTHDF1-stimulated translation of YY1 and MDM2 mRNA. Taken together, our study revealed the novel role of m6A in mediating arsenite-induced human keratinocyte transformation by suppressing p53 activation. This study further sheds light on the mechanisms of arsenic carcinogenesis via RNA epigenetics.