Epigenetic regulation of epithelial-mesenchymal transition by KDM6A histone demethylase in lung cancer cells

Terashima, Minoru; Ishimura, Akihiko; Wanna-udom, Sasithorn; Suzuki, Takeshi

doi:10.1016/j.bbrc.2017.07.048

Cited by 26 publications

(19 citation statements)

References 23 publications

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“…Our data are consistent with previous findings showing that KDM6A inhibits EMT in breast [30] and lung [31] cancers. In the embryo heart, EMT is required to form EPDCs.…”

Section: Discussionsupporting

confidence: 94%

“…Next we explored whether PK2 affect the mesothelial properties of hEPDCs via KDM6A that is a suppressor of EMT in cancer cells [30,31], thereby lowering mesenchymal differentiation of hEPDCs. KDM6A downregulation in hEPDCs did not affect the maintenance of these cells, consistent with a recent report demonstrating that KDM6A knockout has no effect on stem cell pluripotency [32].…”

Section: Epigenetic Regulation Hepdcs Phenotype Via Emtmentioning

confidence: 99%

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A Prokineticin-Driven Epigenetic Switch Regulates Human Epicardial Cell Stemness and Fate

et al. 2018

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Epicardial adipose tissues (EATs) and vascular tissues may both belong to the mesoepithelial lineage that develops from epicardium-derived progenitor cells (EPDCs) in developing and injured hearts. Very little is known of the molecular mechanisms of EPDC contribution in EAT development and neovascularization in adult heart, which the topic remains a subject of intense therapeutic interest and scientific debate. Here we studied the epigenetic control of stemness and anti-adipogenic and pro-vasculogenic fate of human EPDCs (hEPDCs), through investigating an angiogenic hormone, prokineticin-2 (PK2) signaling via its receptor PKR1. We found that hEPDCs spontaneously undergoes epithelial-to-mesenchymal transformation (EMT), and are not predestined for the vascular lineages. However, PK2 via a histone demethylase KDM6A inhibits EMT, and induces asymmetric division, leading to self-renewal and formation of vascular and epithelial/endothelial precursors with angiogenic potential capable of differentiating into vascular smooth muscle and endothelial cells. PK2 upregulates and activates KDM6A to inhibit repressive histone H3K27me3 marks on promoters of vascular genes (Flk-1 and SM22α) involved in vascular lineage commitment and maturation. In PK2-mediated anti-adipogenic signaling, KDM6A stabilizes and increases cytoplasmic β-catenin levels to repress peroxisome proliferator-activated receptor-γ expression and activity. Our findings offer additional molecular targets to manipulate hEPDCs-involved tissue repair/regeneration in cardiometabolic and ischemic heart diseases. Stem Cells 2018;36:1589-1602.

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“…Our data are consistent with previous findings showing that KDM6A inhibits EMT in breast [30] and lung [31] cancers. In the embryo heart, EMT is required to form EPDCs.…”

Section: Discussionsupporting

confidence: 94%

Section: Epigenetic Regulation Hepdcs Phenotype Via Emtmentioning

confidence: 99%

A Prokineticin-Driven Epigenetic Switch Regulates Human Epicardial Cell Stemness and Fate

et al. 2018

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“…S2A and S3A), suggesting the specificity of MEG8 in the control of gene expression. The expression of TWIST was extremely low and not detected in these cells as described previously (29). These results led us to investigate the possibility that the MEG8 effects on EMT-TFs might be due to the regulation of microRNAs because we previously found that MEG3 enhanced ZEB family expression through the repression of the miR-200 family of microRNAs (miR-200a and miR-200c) (19).…”

Section: Meg8 Lncrna-mediated Epigenetic Regulation Of Emtmentioning

confidence: 53%

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

Terashima

Ishimura

Wanna-udom

et al. 2018

Journal of Biological Chemistry

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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-␤ (TGF-␤)-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-␤-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)/Ecadherin. 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-␤ by activating the gene expression program required for EMT. MEG8 knockdown indicated that endogenous MEG8 lncRNA is indispensable for TGF-␤-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.

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“…Through erasing the modification of H3K27me3, ectopic expression of KDM6A could reactivate the transcription of cell adhesion-related genes (51). Other research also indicated that EZH2 could inhibit the transcription of cadherin-1 (CDH1) through direct interaction with H3K27me3; upon EZH2 knockdown (52) or KDM6A overexpression (53), H3K27me3 enriched on CDH1 promoter was deleted and CDH1 transcription was reactivated. Consistent with the aforementioned studies, we also discovered that cell adhesion-related genes, including CDH1, were up-regulated by KDM6A overexpression in bovine embryos.…”

Section: Discussionmentioning

confidence: 99%

H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency

et al. 2019

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Aberrant epigenetic reprogramming is a major factor of developmental failure of cloned embryos. Histone H3 lysine 27 trimethylation (H3K27me3), a histone mark for transcriptional repression, plays important roles in mammalian embryonic development and induced pluripotent stem cell (iPSC) generation. The global loss of H3K27me3 marks may facilitate iPSC generation in mice and humans. However, the H3K27me3 level and its role in bovine somatic cell nuclear transfer (SCNT) reprogramming remain poorly understood. Here, we show that SCNT embryos exhibit global H3K27me3 hypermethylation from the 2‐ to 8‐cell stage and that its removal by ectopically expressed H3K27me3 lysine demethylase (KDM)6A greatly improves nuclear reprogramming efficiency. In contrast, H3K27me3 reduction by H3K27me3 methylase enhancer of zeste 2 polycomb repressive complex knockdown or donor cell treatment with the enhancer of zeste 2 polycomb repressive complex—selective inhibitor GSK343 suppressed blastocyst formation by SCNT embryos. KDM6A overexpression enhanced the transcription of genes involved in cell adhesion and cellular metabolism and X‐linked genes. Furthermore, we identified methyl‐CpG‐binding domain protein 3‐like 2, which was reactivated by KDM6A, as a factor that is required for effective reprogramming in bovines. These results show that H3K27me3 functions as an epigenetic barrier and that KDM6A overexpression improves SCNT efficiency by facilitating transcriptional reprogramming.—Zhou, C., Wang, Y., Zhang, J., Su, J., An, Q., Liu, X., Zhang, M., Wang, Y., Liu, J., Zhang, Y. H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency. FASEB J. 33, 4638–4652 (2019). http://www.fasebj.org

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Epigenetic regulation of epithelial-mesenchymal transition by KDM6A histone demethylase in lung cancer cells

Cited by 26 publications

References 23 publications

A Prokineticin-Driven Epigenetic Switch Regulates Human Epicardial Cell Stemness and Fate

A Prokineticin-Driven Epigenetic Switch Regulates Human Epicardial Cell Stemness and Fate

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

H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency

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