Title: LncRNA MEG3 downregulation mediated by DNMT3b contributes to nickel malignant transformation of human bronchial epithelial cells via modulating PHLPP1 transcription and HIF-1α translation.
Authors: Zhou, C; Huang, C; Wang, J; Huang, H; Li, J; Xie, Q; Liu, Y; Zhu, J; Li, Y; Zhang, D; Zhu, Q; Huang, C
Published In Oncogene, (2017 07 06)
Abstract: 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.
PubMed ID: 28263966
MeSH Terms: Adenocarcinoma of Lung; Adenocarcinoma/enzymology; Adenocarcinoma/pathology; Bronchi/pathology; Carcinogens/toxicity*; Carcinoma, Squamous Cell/enzymology; Carcinoma, Squamous Cell/pathology; Cell Line; Cell Transformation, Neoplastic/chemically induced; Cell Transformation, Neoplastic/metabolism; DNA (Cytosine-5-)-Methyltransferases/physiology*; Down-Regulation; Epithelial Cells/enzymology; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/genetics*; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism; Lung Neoplasms/enzymology; Lung Neoplasms/pathology; Nickel/toxicity*; Nuclear Proteins/genetics; Nuclear Proteins/metabolism*; Phosphoprotein Phosphatases/genetics; Phosphoprotein Phosphatases/metabolism*; Promoter Regions, Genetic; Protein Biosynthesis; RNA, Long Noncoding/genetics*; RNA, Long Noncoding/metabolism; Transcription, Genetic