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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Long noncoding RNAs (lncRNAs) are emerging as key factors 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 a 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, whereas 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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We greatly appreciated Dr Shau-Ping Lin (Institute of Biotechnology, National Taiwan University, Taipei, Taiwan) for his generous gifts about shRNA constructs against MEG3 and control vector. This work was supported partially by grants from NIH/NCI CA112557, CA165980 and CA177665, NIH/NIEHS ES000260, National Natural Science Foundation of China (81441090, 81229002, 81372946, 81673141 and 81371730), the Specialized Research Fund for the Doctoral Program of Higher Education (20133420110001), and the Grant for Scientific Research of BSKY (XJ201418) from Anhui Medical University. We also thank Ms Nedda Tichi for her critical reading of the manuscript.

Author contributions

Conception and design: C Zhou, Q Zhu and C Huang. Acquisition of data (acquired and managed patients, provided facilities, etc.): C Zhou, H Huang, J Li, Q Xie, J Zhu, Y Li, D Zhang, Y Liu and J Wang. Analysis and interpretation of data (for example, statistical analysis, biostatistics and computational analysis): C Zhou, H Huang and C Huang. Writing, review and revision of the manuscript: C Zhou and C Huang. Administrative, technical or material support (that is, reporting or organizing data, constructing databases): C Zhou, J Li, Q Zhu, and C Huang. Study supervision: C Huang.

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Correspondence to Q Zhu or C Huang.

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Supplementary Information accompanies this paper on the Oncogene website

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