LncRNA MEG3 downregulation mediated by DNMT3b contributes to nickel malignant transformation of human bronchial epithelial cells via modulating PHLPP1 transcription and HIF-1α translation.
LncRNA MEG3 downregulation mediated by DNMT3b contributes to nickel malignant transformation of human bronchial epithelial cells via modulating PHLPP1 transcription and HIF-1α translation.
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DNMT3b介导的LncRNA MEG3下调通过调节PHLPP1转录和HIF-1α翻译导致人支气管上皮细胞镍恶性转化
DOI：
10.1038/onc.2017.14
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发表时间：
2017-07-06
期刊：
影响因子：
8
通讯作者：
Huang C
中科院分区：
文献类型：
--
作者：
Zhou C;Huang C;Wang J;Huang H;Li J;Xie Q;Liu Y;Zhu J;Li Y;Zhang D;Zhu Q;Huang C
长链非编码RNA（lncRNA）在各种基本的细胞生物学过程中起着关键作用，其中许多可能在肿瘤发生中起着重要作用。母系表达基因3（MEG3）是位于14q32的印迹基因，编码lncRNA，并且已经报道了MEG3在多种癌组织中表达降低。然而，MEG3在环境致癌物诱导的肺肿瘤发生中的改变和作用尚不清楚。本研究首次发现环境致癌物镍暴露导致MEG3表达下调，进而启动c-Jun介导的PHLPP1转录抑制和缺氧诱导因子-1 α（HIF-1 α）蛋白翻译上调，进而导致人支气管上皮细胞恶性转化。MEG3下调的机制是通过镍诱导DNMT3b表达而引起的启动子甲基化，而PHLPP 1转录抑制的机制是MEG3与其抑制性转录因子c-Jun的相互作用减弱，此外，镍诱导PHLPP 1抑制后激活Akt/p70S6K/S6轴而上调HIF-1 α蛋白的翻译。总之，我们发现镍暴露导致DNMT3b诱导和MEG3启动子高甲基化和表达抑制，进一步降低其与c-Jun的结合，进而增加c-Jun对PHLPP 1转录的抑制，导致Akt/p70 S6 K/S6轴激活，HIF-1 α蛋白翻译以及人支气管上皮细胞的恶性转化。我们的研究为了解MEG3在镍诱导的肺肿瘤发生中的变化和作用提供了重要的见解。
Long noncoding RNAs (lncRNAs) are emerging as key players in various fundamental cellular biological processes, and many of them are likely to have functional roles in tumorigenesis. Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 that encodes an lncRNA, and the decreased MEG3 expression has been reported in multiple cancer tissues. However, nothing is known about the alteration and role of MEG3 in environmental carcinogen-induced lung tumorigenesis. Our present study, for the first time to the best of our knowledge, discovered that environmental carcinogen nickel exposure led to MEG3 downregulation, consequently initiating c-Jun-mediated PHLPP1 transcriptional inhibition and hypoxia-inducible factor-1α (HIF-1α) protein translation upregulation, in turn resulting in malignant transformation of human bronchial epithelial cells. Mechanistically, MEG3 downregulation was attributed to nickel-induced promoter hypermethylation via elevating DNMT3b expression, while PHLPP1 transcriptional inhibition was due to the decreasing interaction of MEG3 with its inhibitory transcription factor c-Jun. Moreover, HIF-1α protein translation was upregulated via activating the Akt/p70S6K/S6 axis resultant from PHLPP1 inhibition in nickel responses. Collectively, we uncover that nickel exposure results in DNMT3b induction and MEG3 promoter hypermethylation and expression inhibition, further reduces its binding to c-Jun and in turn increasing c-Jun inhibition of PHLPP1 transcription, leading to the Akt/p70S6K/S6 axis activation, and HIF-1α protein translation as well as malignant transformation of human bronchial epithelial cells. Our studies provide a significant insight into understanding the alteration and role of MEG3 in nickel-induced lung tumorigenesis.
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