Inhibitors of enhancer of zeste homolog 2 (EZH2) activate tumor-suppressor microRNAs in human cancer cells

Hibino, Sana; Saito, Yoshimasa; Muramatsu, Tadashi; Otani, A; Kasai, Y; Kimura, Masaki; Saito, Hidetsugu

doi:10.1038/oncsis.2014.17

Cited by 62 publications

(52 citation statements)

References 46 publications

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“…Previous studies have showed that EZH2 was overexpressed in a variety of human cancers, which enhanced tumorigenesis through various signaling pathways [23]. In our study, downregulation of lncRNA-ANCR decreased the expression abundance of EZH2, suggesting that lncRNA-ANCR positively regulates the expression of EZH2.…”

Section: Discussionsupporting

confidence: 64%

LncRNA-ANCR regulates the cell growth of osteosarcoma by interacting with EZH2 and affecting the expression of p21 and p27

Zhang

Peng

2017

J Orthop Surg Res

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BackgroundOsteosarcoma (OS) is one of the most common malignant tumors developed in the bone. EZH2 has been found to play pivotal roles in the development of various cancers. LncRNA-ANCR (anti-differentiation ncRNA) has been reported to interact with EZH2 and regulated osteoblast differentiation. Our study aimed to investigate the effect of lncRNA-ANCR on the tumorigenesis of osteosarcoma and explore the underlying molecular mechanism.MethodsRT-PCR was performed to detect the messenger RNA (mRNA) levels of lncRNA-ANCR, EZH2, p21, and p27 in OS tissues and cell lines. The cell proliferation, transwell invasion, and migration assays were conducted to evaluate the influence of lncRNA-ANCR depletion on the growth of OS cells. RNA pull-down assay was carried out to detect the interaction between lncRNA-ANCR and EZH2. Correlation between the expression of lncRNA-ANCR and the expression of EZH2 were analyzed by cross-tabulation.ResultsLncRNA-ANCR is highly expressed in both OS tissues and cell lines. Reduced expression of lncRNA-ANCR inhibited the cell proliferation, invasion, and migration of OS cells. The cell apoptosis rate was also increased with the overexpression of lncRNA-ANCR. Mechanistically, downregulation of lncRNA-ANCR reduced the mRNA level of EZH2 and increased the expression of p21 and p27 at both mRNA and protein levels. LncRNA-ANCR interacted with EZH2 and their expression abundance was positively correlated in OS patients.ConclusionLncRNA-ANCR inhibited the cell proliferation, migration, and invasion of OS cells possibly through interacting with EZH2 and regulating the expression of p21 and p27.

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Section: Discussionsupporting

confidence: 64%

LncRNA-ANCR regulates the cell growth of osteosarcoma by interacting with EZH2 and affecting the expression of p21 and p27

Zhang

Peng

2017

J Orthop Surg Res

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“…Because renal EMT and subsequent G 2 /M arrest are pivotal processes associated with overproduction of profibrotic cytokines and induction of renal fibrosis, EZH2 inhibitors would have therapeutic potential for treatment of renal fibrosis. Currently, several compounds for inhibition of EZH2 have been developed and are widely used in preclinical and in vitro studies to investigate the function of EZH2 in cancers and other diseases (60), and our data suggest a possible benefit from a clinical trial of treatment of renal fibrosis by EZH2 inhibition.…”

Section: Discussionmentioning

confidence: 73%

Targeting histone methyltransferase enhancer of zeste homolog‐2 inhibits renal epithelial‐mesenchymal transition and attenuates renal fibrosis

et al. 2018

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Enhancer of zeste homolog-2 (EZH2) is a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types. Its role in renal epithelial-mesenchymal transition (EMT) remains unknown. In this study, we found that EZH2 and H3K27me3 were highly expressed in mouse kidney with unilateral ureteral obstruction and cultured mouse kidney proximal tubular (TKPT) cells undergoing EMT. Inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) attenuated renal fibrosis, which was associated with preserving E-cadherin expression and inhibiting Vimentin up-regulation in the obstructed kidney. Treatment with 3-DZNeP or transfection of EZH2 siRNA also inhibited TGF-β1-induced EMT of TKPT cells. Injury to the kidney or cultured TKPT cells resulted in up-regulation of Snail-l family transcriptional repressor (Snail)-1 and Twist family basic helix-loop-helix (BHLH) transcription factor (Twist)-1, which are 2 transcription factors, and down-regulation of phosphatase and tensin homolog, a protein tyrosine phosphatase associated with inhibition of PI3K-protein kinase B (AKT) signaling; EZH2 inhibition or silencing reversed all those responses. 3-DZNeP was also effective in suppressing epithelial arrest at the G/M phase and dephosphorylating AKT and β-catenin in vivo and in vitro. These data indicate that EZH2 activation contributes to renal EMT and fibrosis through activation of multiple signaling pathways and suggest that EZH2 has potential as a therapeutic target for treatment of renal fibrosis.-Zhou, X., Xiong, C., Tolbert, E., Zhao, T. C., Bayliss, G., Zhuang, S. Targeting histone methyltransferase enhancer of zeste homolog-2 inhibits renal epithelial-mesenchymal transition and attenuates renal fibrosis.

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“…33 Currently, this compound is widely used in preclinical and in vitro studies to investigate the function of EZH2 in cancer and has been shown to effectively inhibit cell proliferation, reverse epithelial-to-mesenchymal transition, and prevent tumor progression. 34 However, it remains unclear whether targeting suppression of EZH2 can also interfere with renal interstitial fibroblast activation and renal fibrosis development. (A and E) Normally cultured NRK-49F cells were treated with 3-DZNeP (0-10 mM) for 36 hours.…”

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confidence: 99%

Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression

Zhou

Zang

Ponnusamy

et al. 2015

JASN

149

158

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Enhancer of zeste homolog 2 (EZH2) is a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types. However, the role of EZH2 in renal fibrogenesis remains unexplored. In this study, we found high expression of EZH2 and H3K27me3 in cultured renal fibroblasts and fibrotic kidneys from mice with unilateral ureteral obstruction and humans with CKD. Pharmacologic inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) or GSK126 or siRNAmediated silencing of EZH2 inhibited serum-and TGFb1-induced activation of renal interstitial fibroblasts in vitro, and 3-DZNeP administration abrogated deposition of extracellular matrix proteins and expression of a-smooth muscle actin in the obstructed kidney. Injury to the kidney enhanced Smad7 degradation, Smad3 phosphorylation, and TGFb receptor 1 expression, and 3-DZNeP administration prevented these effects. 3-DZNeP also suppressed phosphorylation of the renal EGF and PDGFb receptors and downstream signaling molecules signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 after injury. Moreover, EZH2 inhibition increased the expression of phosphatase and tensin homolog (PTEN), a protein previously associated with dephosphorylation of tyrosine kinase receptors in the injured kidney and serum-stimulated renal interstitial fibroblasts. Finally, blocking PTEN with SF1670 largely diminished the inhibitory effect of 3-DZNeP on renal myofibroblast activation. These results uncovered the important role of EZH2 in mediating the development of renal fibrosis by downregulating expression of Smad7 and PTEN, thus activating profibrotic signaling pathways. Targeted inhibition of EZH2, therefore, could be a novel therapy for treating CKD.

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Inhibitors of enhancer of zeste homolog 2 (EZH2) activate tumor-suppressor microRNAs in human cancer cells

Cited by 62 publications

References 46 publications

LncRNA-ANCR regulates the cell growth of osteosarcoma by interacting with EZH2 and affecting the expression of p21 and p27

LncRNA-ANCR regulates the cell growth of osteosarcoma by interacting with EZH2 and affecting the expression of p21 and p27

Targeting histone methyltransferase enhancer of zeste homolog‐2 inhibits renal epithelial‐mesenchymal transition and attenuates renal fibrosis

Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression

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