Journal Article

LncRNA MEG3 downregulation mediated by DNMT3b contributes to nickel malignant transformation of human bronchial epithelial cells via modulating PHLPP1 transcription and HIF-1α translation

Liu, Y, Zhou, C, Zhang, D, Wang, J, Huang, C, Zhu, Q, Huang, H, Li, J, Li, Y, Xie, Q, Zhu, J

2017

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/109 / 38/22 / 38/77 / 38/89 / 631/67/1612/1350 / 631/80/86 / 82/1 / 82/80 / 96/1 / 96/95 / Adenocarcinoma - enzymology / Adenocarcinoma - pathology / Adenocarcinoma of Lung / AKT protein / Apoptosis / Bronchi - pathology / c-Jun protein / Carcinogens / Carcinogens - toxicity / Carcinoma, Squamous Cell - enzymology / Carcinoma, Squamous Cell - pathology / Cell Biology / Cell Line / Cell Transformation, Neoplastic - chemically induced / Cell Transformation, Neoplastic - metabolism / Chromosome 14 / DNA (Cytosine-5-)-Methyltransferases - physiology / DNA Methyltransferase 3B / Down-Regulation / Epithelial cells / Epithelial Cells - enzymology / Gene Expression Regulation, Neoplastic / Genetic transformation / Human Genetics / Humans / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Hypoxia-inducible factor 1a / Internal Medicine / Lung cancer / Lung Neoplasms - enzymology / Lung Neoplasms - pathology / Medicine / Medicine & Public Health / Nickel / Nickel - toxicity / Non-coding RNA / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Oncology / original-article / Phosphoprotein Phosphatases - genetics / Phosphoprotein Phosphatases - metabolism / Promoter Regions, Genetic / Protein Biosynthesis / Proteins / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / Transcription factors / Transcription, Genetic / Translation / Tumorigenesis