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 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.

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

“…The patient characteristics are shown in Supplemental Table 1 (supplemental material available online with this article; https://doi.org/10.1172/JCI96218DS1). As shown in Figure 1A, the microarray analysis identified 158 upregulated and 142 downregulated lncRNAs from 7,419 analyzed lncRNAs in the MIBC tissues, including CASC9, MIAT, MEG3, and LINC01133, which are associated with human cancer progression (25)(26)(27)(28). Additionally, one lncRNA (LINC00958, RefSeq accession number NR_038904), Figure 1.…”

lncRNA FAM83H‑AS1 is associated with the prognosis of colorectal carcinoma and promotes cell proliferation by targeting the Notch signaling pathway

“…lncRNAs have been reported to be involved in a variety of biological processes, including tumorigenesis through regulating oncogenes or tumor suppressors at several levels (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). For example, Xia et al (13) demonstrated that long noncoding RNA papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) inhibited proliferation and invasion of glioma cells by suppressing the Wnt/β-catenin signaling pathway.…”

lncRNA SNHG5 is associated with poor prognosis of bladder cancer and promotes bladder cancer cell proliferation through targeting p27

“…For instance, in 2017, Idogawa et al reported that long non-coding RNA NEAT1 was a transcriptional target of p53 and modulated p53-induced transactivation and tumor-suppressor function (10). Zhou et al demonstrated that downregulation of lncRNA MEG3 mediated by DNMT3b contributed to nickel malignant transformation of human bronchial epithelial cells via modulating PHLPP1 transcription and HIF-1α translation (11). Wang et al uncovered that 2-O-Methylmagnolol upregulated the long non-coding RNA, GAS5, and enhanced apoptosis in skin cancer cells (12).…”