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.
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.
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China.|Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.|Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Huang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Cardiothoracic Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.|Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Huang
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D001980:Bronchi / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology*; D015536:Down-Regulation; D004847:Epithelial Cells / Q000201:enzymology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology; D009532:Nickel / Q000633:toxicity*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000097584:DNA Methyltransferase 3B
chemical_list: D002273:Carcinogens; D004248:DNA (Cytosine-5-)-Methyltransferases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009532:Nickel; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases; D062085:RNA, Long Noncoding; D000097584:DNA Methyltransferase 3B; C497442:HIF1A protein, human; C498907:MEG3 non-coding RNA, human; C400601:PHLPP1 protein, human