YTHDF2 promotes arsenic-induced malignant phenotypes by degrading PIDD1 mRNA in human keratinocytes.

Qian Zhang, Jin Man, Tianhe Zhao, Donglei Sun, Zunzhen Zhang
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Abstract

Arsenic is a widespread environmental carcinogen, and its carcinogenic mechanism has been the focus of toxicology. N6-methyladenosine (m6A) binding protein YTH domain family protein 2 (YTHDF2) performs various biological functions by degrading m6A-modified mRNAs. However, the m6A-modified target mRNA of YTHDF2 in regulating arsenic carcinogenesis remains largely unknown. To explore the effect of YTHDF2 in regulating arsenic carcinogenicity, we exposed the human keratinocyte HaCaT cells to 1 μM sodium arsenite for 50 generations to create a cell model of arsenic carcinogenesis (HaCaT-T). Our results demonstrated that YTHDF2 protein levels were higher in HaCaT-T cells than HaCaT cells, and knockdown of YTHDF2 significantly inhibited arsenic-induced malignant phenotypes. In addition, m6A levels in HaCaT-T cells were remarkably elevated, accompanied by abnormal expression of m6A methyltransferases and m6A demethylases. Mechanistically, YTHDF2 bound to p53-induced death domain protein 1 (PIDD1) mRNA in an m6A-dependent manner, thereby promoting the degradation of PIDD1 mRNA. Moreover, the decay of PIDD1 mRNA inhibited the formation of PIDDosome complex that is essential for activating the apoptosis initiator caspase-2, leading to a decrease in caspase-2-dependent mitochondrial apoptosis and subsequently promoting the malignant phenotypes of HaCaT-T cells. Collectively, our study reveals the role of YTHDF2 in arsenic-induced malignant phenotypes of human keratinocytes through direct interaction with PIDD1 mRNA in an m6A-dependent manner, which provides new insight into the precise mechanism underlying arsenic-induced skin cancer.

YTHDF2通过降解人角质形成细胞中的PIDD1 mRNA促进砷诱导的恶性表型。
砷是一种广泛存在的环境致癌物质,其致癌机制一直是毒理学研究的重点。N6-甲基腺苷(m6A)结合蛋白YTH结构域家族蛋白2(YTHDF2)通过降解m6A修饰的mRNA发挥多种生物学功能。然而,YTHDF2在调控砷致癌过程中的m6A修饰靶mRNA仍是未知数。为了探索 YTHDF2 在调控砷致癌中的作用,我们将人类角质形成细胞 HaCaT 细胞暴露于 1 μM 亚砷酸钠中 50 代,建立了砷致癌细胞模型(HaCaT-T)。我们的结果表明,HaCaT-T细胞中的YTHDF2蛋白水平高于HaCaT细胞,敲除YTHDF2能显著抑制砷诱导的恶性表型。此外,HaCaT-T 细胞中的 m6A 含量明显升高,并伴有 m6A 甲基转移酶和 m6A 去甲基化酶的异常表达。从机理上讲,YTHDF2以m6A依赖的方式与p53诱导的死亡结构域蛋白1(PIDD1)mRNA结合,从而促进了PIDD1 mRNA的降解。此外,PIDD1 mRNA的降解抑制了PIDDosome复合物的形成,而PIDDosome复合物对激活凋亡启动子caspase-2至关重要,从而导致依赖caspase-2的线粒体凋亡减少,进而促进了HaCaT-T细胞恶性表型的形成。总之,我们的研究揭示了 YTHDF2 通过与 PIDD1 mRNA 以 m6A 依赖性方式直接相互作用,在砷诱导的人类角朊细胞恶性表型中的作用,这为了解砷诱导皮肤癌的确切机制提供了新的视角。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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