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首页> 外文期刊>Cell cycle >JNK and STAT3 signaling pathways converge on Akt-mediated phosphorylation of EZH2 in bronchial epithelial cells induced by arsenic
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JNK and STAT3 signaling pathways converge on Akt-mediated phosphorylation of EZH2 in bronchial epithelial cells induced by arsenic

机译：JNK和STAT3信号通路在砷诱导的支气管上皮细胞中Akt介导的EZH2磷酸化上趋同

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摘要

The molecular mechanisms by which arsenic (As3+) causes human cancers remain to be fully elucidated. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb-repressive complexes 2 (PRC2) that promotes trimethylation of lysine 27 of histone H3, leading to altered expression of tumor suppressors or oncogenes. In the present study, we determined the effect of As3+ on EZH2 phosphorylation and the signaling pathways important for As3+-induced EZH2 phosphorylation in human bronchial epithelial cell line BEAS-2B. The involvement of kinases in As3+-induced EZH2 phosphorylation was validated by siRNA-based gene silencing. The data showed that As3+ can induce phosphorylation of EZH2 at serine 21 in human bronchial epithelial cells and that the phosphorylation of EZH2 requires an As3+-activated signaling cascade from JNK and STAT3 to Akt. Transfection of the cells with siRNA specific for JNK1 revealed that JNK silencing reduced serine727 phosphorylation of STAT3, Akt activation and EZH2 phosphorylation, suggesting that JNK is the upstream kinase involved in As 3+-induced EZH2 phosphorylation. Because As3+ is capable of inducing miRNA-21 (miR-21), a STAT3-regulated miRNA that represses protein translation of PTEN or Spry2, we also tested the role of STAT3 and miR-21 in As3+-induced EZH2 phosphorylation. Ectopic overexpression of miR-21 promoted Akt activation and phosphorylation of EZH2, whereas inhibiting miR-21 by transfecting the cells with anti-miR-21 inhibited Akt activation and EZH2 phosphorylation. Taken together, these results demonstrate a contribution of the JNK, STAT3 and Akt signaling axis to As3+-induced EZH2 phosphorylation. Importantly, these findings may reveal new molecular mechanisms underlying As3+-induced carcinogenesis.
机译：砷（As3 +）引起人类癌症的分子机制仍有待阐明。 zeste同源物2（EZH2）的增强子是多梳抑制复合物2（PRC2）的催化亚基，可促进组蛋白H3赖氨酸27的三甲基化，从而导致肿瘤抑制物或癌基因表达的改变。在本研究中，我们确定了As3 +对EZH2磷酸化的影响以及对人支气管上皮细胞株BEAS-2B中As3 +诱导的EZH2磷酸化重要的信号通路。通过基于siRNA的基因沉默验证了激酶参与As3 +诱导的EZH2磷酸化。数据显示，As3 +可以诱导人支气管上皮细胞中21号丝氨酸的EZH2磷酸化，并且EZH2的磷酸化需要从JNK和STAT3到Akt的As3 +激活信号级联。用对JNK1特异的siRNA转染细胞表明，JNK沉默降低了STAT3的丝氨酸727磷酸化，Akt激活和EZH2磷酸化，表明JNK是参与As 3+诱导的EZH2磷酸化的上游激酶。由于As3 +能够诱导miRNA-21（miR-21），这是一种STAT3调控的miRNA，可抑制PTEN或Spry2的蛋白质翻译，因此我们还测试了STAT3和miR-21在As3 +诱导的EZH2磷酸化中的作用。 miR-21的异位过表达促进了EZH2的Akt活化和磷酸化，而通过用抗miR-21转染细胞来抑制miR-21则抑制了Akt活化和EZH2磷酸化。综上所述，这些结果证明了JNK，STAT3和Akt信号转导轴对As3 +诱导的EZH2磷酸化的贡献。重要的是，这些发现可能揭示了As3 +诱导的致癌作用的新分子机制。

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