MEG3 Long Noncoding RNA Contributes to the Epigenetic Regulation of Epithelial-Mesenchymal Transition in Lung Cancer Cell Lines

Abstract

Histone methylation is implicated in a number of biological and pathological processes, including cancer development. In this study, we investigated the molecular mechanism for the recruitment of Polycomb repressive complex-2 (PRC2) and its accessory component, JARID2, to chromatin, which regulates methylation of lysine 27 of histone H3 (H3K27), during epithelial-mesenchymal transition (EMT) of cancer cells. The expression of MEG3 long noncoding RNA (lncRNA), which could interact with JARID2, was clearly increased during transforming growth factor-β (TGF-β)-induced EMT of human lung cancer cell lines. Knockdown of MEG3 inhibited TGF-β-mediated changes in cell morphology and cell motility characteristic of EMT and counteracted TGF-β-dependent changes in the expression of EMT-related genes such as CDH1, ZEB family, and the microRNA-200 family. Overexpression of MEG3 influenced the expression of these genes and enhanced the effects of TGF-β in their expressions. Chromatin immunoprecipitation (ChIP) revealed that MEG3 regulated the recruitment of JARID2 and EZH2 and histone H3 methylation on the regulatory regions of CDH1 and microRNA-200 family genes for transcriptional repression. RNA immunoprecipitation and chromatin isolation by RNA purification assays indicated that MEG3 could associate with JARID2 and the regulatory regions of target genes to recruit the complex. This study demonstrated a crucial role of MEG3 lncRNA in the epigenetic regulation of the EMT process in lung cancer cells.

Intracellular and extracellular TGF-β signaling in cancer: some recent topics

“…Mathematical predictions and experimental confirmation suggest that feedback loops between transcription factors and miRNAs function as reversible switches to promote TGF-β-induced EMT in a stepwise manner [73][74][75]. lncRNAs also contribute to TGF-β-induced EMT [76][77][78]. TGF-β-induced lncRNA-ATB (activated by TGF-β) enhances ZEB1 and ZEB2 expression by binding to the miR-200 family in hepatocellular carcinoma [76].…”

“…Indeed, chromatin accessibility and epigenetic modifications are altered during the EMT process [93,123], and emerging roles of lncRNAs in the regulation of histone modification have been revealed. A lncRNA MEG3 is induced by TGF-β and involved in the process of EMT in lung adenocarcinoma cells through recruitment of polycomb repressive complex 2 (PRC2) and its accessory component jumonji and ATrich interaction domain containing 2 (JARID2) to the promoter regions of CDH1 (encoding E-cadherin) and MIR200 family genes (encoding the miR-200 family) to induce tri-methylation of lysine 27 of histone H3 (H3K27) [78]. In Smad signaling, the binding regions of the Smad family in the genome are strikingly different depending on the cellular context [124,125].…”

MEG3 affects the progression and chemoresistance of T‐cell lymphoblastic lymphoma by suppressing epithelial‐mesenchymal transition via the PI3K/mTOR pathway

“…For example, MEG3 has been proved to inhibit the invasion and migration of thyroid cancer cells by targeting Rac1 . In addition, MEG3 has also been shown to play an important role in the EMT of breast cancer, lung cancer, and bladder cancer . Similarly, MEG3 has also been shown to affect the drug resistance of lung, ovarian, and colon cancers .…”

Comprehensive Analysis of Differentially Expressed Profiles of lncRNAs/mRNAs and miRNAs with Associated ceRNA Networks in Triple-Negative Breast Cancer

“…Compared with protein coding gene, lncRNAs are considered to have a high tissue-and disease-specific expression patterns, moreover, their expressions are more closely related to tumor grade and stage [17]. In recent years, some dysregulated lncRNAs in various cancers including gastric cancer, lung cancer, breast cancer, etc., have been discovered by transcriptional profile analysis and experimental researches, highlighting their potential roles as novel biomarkers and therapeutic targets for cancers [18][19][20]. However, genomewide screen of the expression of lncRNAs and validation to elucidate the functions of specific lncRNAs and clinical implications by integrated miRNA and mRNA expression profiles in TNBC based on large-scale RNA-seq data has not been reported so far.…”