MEG8 long noncoding RNA contributes to epigenetic progression of the epithelial-mesenchymal transition of lung and pancreatic cancer cells

J Biol Chem. 2018 Nov 23;293(47):18016-18030. doi: 10.1074/jbc.RA118.004006. Epub 2018 Sep 27.

Abstract

Long noncoding RNAs (lncRNAs) are important regulatory molecules in various biological and pathological processes, including cancer development. We have previously shown that the MEG3 lncRNA plays an essential role in transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition (EMT) of human lung cancer cells. In this study, we investigated the function of another lncRNA, MEG8, which shares the DLK1-DIO3 locus with MEG3, in the regulation of EMT. MEG8 lncRNA expression was immediately induced during TGF-β-mediated EMT of A549 and LC2/ad lung cancer and Panc1 pancreatic cancer cell lines. MEG8 overexpression specifically suppressed the expression of microRNA-34a and microRNA-203 genes, resulting in up-regulation of SNAIL family transcriptional repressor 1 (SNAI1) and SNAI2 transcription factors, which repressed expression of cadherin 1 (CDH1)/E-cadherin. Mechanistic investigations revealed that MEG8 associates with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) protein and induces its recruitment to the regulatory regions of the two microRNA genes for histone H3 methylation and transcriptional repression. Interestingly, expression of both MEG8 and MEG3, but not each individually, could induce EMT-related cell morphological changes and increased cell motility in the absence of TGF-β by activating the gene expression program required for EMT. MEG8 knockdown indicated that endogenous MEG8 lncRNA is indispensable for TGF-β-induced EMT in A549 lung cancer and Panc1 pancreatic cancer cells. Our findings indicate that MEG8 lncRNA significantly contributes to epigenetic EMT induction and increase our understanding of the lncRNA-mediated regulatory mechanisms involved in malignant progression of cancer.

Keywords: cancer biology; chromatin; epigenetics; epithelial-mesenchymal transition (EMT); histone methylation; long noncoding RNA (long ncRNA, lncRNA); metastasis; transcription regulation; transforming growth factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Epigenesis, Genetic
  • Epithelial Cells / metabolism
  • Epithelial-Mesenchymal Transition*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / physiopathology*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / physiopathology*
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism
  • Transforming Growth Factor beta1

Substances

  • Cadherins
  • MEG3 non-coding RNA, human
  • MIRN203 microRNA, human
  • MIRN34 microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • SNAI1 protein, human
  • SNAI2 protein, human
  • Snail Family Transcription Factors
  • Transforming Growth Factor beta1