The enhancer of zeste homolog 2 (EZH2), a potential therapeutic target, is regulated by miR-101 in renal cancer cells

Sakurai, Toshihiko; Bilim, Vladimir; Ugolkov, Andrey; Yuuki, Kaori; Tsukigi, Masaaki; Motoyama, Teiichi; Tomita, Yoshihiko

doi:10.1016/j.bbrc.2012.05.035

Cited by 49 publications

(36 citation statements)

References 26 publications

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“…9,37,38 The best characterized of these is miR-101. 39 Consistent with the effect of miR-101 in inhibiting EZH2 translation, we observed a profound increase in EZH2 protein in podocytes exposed to an oligonucleotide inhibitor of this miR. Moreover, enhanced EZH2 translation mediated through inhibition of miR-101 was accompanied by an attenuation in both TxnIP expression and ROS accumulation.…”

Section: Discussionsupporting

confidence: 84%

The Histone Methyltransferase Enzyme Enhancer of Zeste Homolog 2 Protects against Podocyte Oxidative Stress and Renal Injury in Diabetes

Siddiqi

Majumder

Thai

et al. 2015

JASN

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Epigenetic regulation of oxidative stress is emerging as a critical mediator of diabetic nephropathy. In diabetes, oxidative damage occurs when there is an imbalance between reactive oxygen species generation and enzymatic antioxidant repair. Here, we investigated the function of the histone methyltransferase enzyme enhancer of zeste homolog 2 (EZH2) in attenuating oxidative injury in podocytes, focusing on its regulation of the endogenous antioxidant inhibitor thioredoxin interacting protein (TxnIP). Pharmacologic or genetic depletion of EZH2 augmented TxnIP expression and oxidative stress in podocytes cultured under high-glucose conditions. Conversely, EZH2 upregulation through inhibition of its regulatory microRNA, microRNA-101, downregulated TxnIP and attenuated oxidative stress. In diabetic rats, depletion of EZH2 decreased histone 3 lysine 27 trimethylation (H3K27me3), increased glomerular TxnIP expression, induced podocyte injury, and augmented oxidative stress and proteinuria. Chromatin immunoprecipitation sequencing revealed H3K27me3 enrichment at the promoter of the transcription factor Pax6, which was upregulated on EZH2 depletion and bound to the TxnIP promoter, controlling expression of its gene product. In high glucose-exposed podocytes and the kidneys of diabetic rats, the lower EZH2 expression detected coincided with upregulation of Pax6 and TxnIP. Finally, in a gene expression array, TxnIP was among seven of 30,854 genes upregulated by high glucose, EZH2 depletion, and the combination thereof. Thus, EZH2 represses the transcription factor Pax6, which controls expression of the antioxidant inhibitor TxnIP, and in diabetes, downregulation of EZH2 promotes oxidative stress. These findings expand the extent to which epigenetic processes affect the diabetic kidney to include antioxidant repair.

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Section: Discussionsupporting

confidence: 84%

The Histone Methyltransferase Enzyme Enhancer of Zeste Homolog 2 Protects against Podocyte Oxidative Stress and Renal Injury in Diabetes

Siddiqi

Majumder

Thai

et al. 2015

JASN

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“…P27, a cyclin-dependent kinase inhibitor, has been reported as a target gene of EZH2 in several carcinoma types (15,16). In line with these findings, the present study confirmed that in hepatoblastoma tissues with EZH2 overexpression, p27 expression was downregulated, and that depletion of EZH2 in hepatoblastoma cell lines increased the expression of p27.…”

Section: Discussionsupporting

confidence: 90%

Enhancer of zeste homolog 2 depletion arrests the proliferation of hepatoblastoma cells

Wang

Xiao²,

Chen

et al. 2016

Molecular Medicine Reports

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Abstract. Hepatoblastoma is the most common type of malignant liver tumor in children. While outcomes have been greatly improved in the past decades, the treatment of advanced hepatoblastoma has remained challenging. Enhancer of zeste homologue 2 (EZH2), a member of the polycomb group regulators of gene activity, is amplified and overexpressed in a variety of cancers. However, the role of EZH2 in hepatoblastoma has remained to be fully elucidated. The purpose of the present study was to investigate the expression patterns of EZH2 in hepatoblastoma cells and to assess the anti-cancer effects of EZH2 depletion. Western blot analysis revealed that EZH2 expression was significantly higher in hepatoblastoma specimens compared with that in peri-tumor tissues, while p27 was reduced in hepatoblastoma. Suppression of EHZ2 using lentiviral small hairpin RNA inhibited hepatoblastoma cell proliferation, induced cell cycle arrest in G1 phase and enhanced the expression of G1/S-phase checkpoint protein p27. These results suggested that EZH2 may represent a potential diagnostic marker and therapeutic target for the treatment of hepatoblastoma.

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“…interest in basic and clinical studies of cancer. Several studies have demonstrated that EZH2 protein is highly expressed in RCC tissues (33)(34)(35)(36), the level of which is associated with RCC dedifferentiation, suggesting that the EZH2 protein may contribute to RCC progression and metastasis. More recently, studies have indicated that EZH2 protein is highly expressed in prostate cancer tissues, which are also associated with a high rate of metastasis to the bone (16,37,38).…”

Section: Discussionmentioning

confidence: 99%

Alterations in enhancer of zeste homolog 2, matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression are associated with ex vivo and in vitro bone metastasis in renal cell carcinoma

Wang

Ren

Guo

et al. 2015

Molecular Medicine Reports

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Abstract. Renal cell carcinoma (RCC) has a high potential for bone metastasis; however, the molecular mechanisms underlying this metastasis have remained to be elucidated. The present study aimed to explore the expression levels of enhancer of zeste homolog 2 (EZH2), matrix metalloproteinase-2 (MMP2) and tissue inhibitor of metalloproteinase-2 (TIMP2) as determinants of RCC-associated bone metastasis. Their expression was evaluated in a newly generated RCC cell subline that has a high potential for bone metastasis, in tissue specimens from metastasized bone tissues from patients with RCC and in RCC tissues without metastasis. A total of 25 RCC tissue specimens without metastasis and 13 RCC tissue specimens with bone metastasis were acquired for immunohistochemical analysis of EZH2, MMP2 and TIMP2 protein expression. The expression levels of EZH2, MMP2 and TIMP2 mRNA and protein were analyzed in the ACHN and ACHN-BO5 cell lines using western blot and reverse transcription polymerase chain reaction (PCR) analyses. Methylation-specific PCR was also used to analyze TIMP2 promoter methylation. EZH2 and MMP2 proteins were found to be expressed at higher levels in tissues from patients where RCC had metastasized to the bone as compared with those in RCC patients without metastasis, whereas there was no significant difference in the expression of TIMP2 protein between the two tissues. Furthermore, the expression of EZH2 protein was correlated with MMP2 expression, but there was no significant correlation between the expression of EZH2 and TIMP2 proteins. The in vitro results using cell lines confirmed the ex vivo findings, indicating that the expression levels of EZH2 and MMP2 protein and mRNA were higher in ACHN-BO5 cells than those in ACHN cells. By contrast, TIMP2 protein and mRNA expression levels were lower in ACHN-BO5 cells than those in the parental ACHN cells. The TIMP2 promoter was highly methylated in ACHN-BO5 cells compared with that in ACHN cells. Upregulation of EZH2, MMP2 and TIMP2 expression was correlated with metastasis of RCC to bone tissues ex vivo and in vitro. Further studies are required in order to elucidate the mechanism underlying the altered expression of these genes. IntroductionRenal cell carcinoma (RCC), which has been suggested to originate from the renal tubules and collecting tube epithelial cells, accounts for 85% of malignant kidney neoplasms and ~2% of all human malignancies (1,2). RCC is a pathologically heterogeneous disease, which can be classified into clear, papillary, granular, spindle and mixed cell subtypes based on certain cytoplasmic features (3). RCC morbidity increases by 2% annually and mortality has reached ~100,000 cases/year worldwide (4). Approximately 30% of patients with RCC develop metastatic disease, most frequently in the lungs, bones or brain (5). A clinical study confirmed that osteolysis represented 30% of the total metastatic disease cases associated with RCC (6). The incidence rate of bone tissue metastasis was higher in autopsy data from patients with RCC (5...

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The enhancer of zeste homolog 2 (EZH2), a potential therapeutic target, is regulated by miR-101 in renal cancer cells

Cited by 49 publications

References 26 publications

The Histone Methyltransferase Enzyme Enhancer of Zeste Homolog 2 Protects against Podocyte Oxidative Stress and Renal Injury in Diabetes

The Histone Methyltransferase Enzyme Enhancer of Zeste Homolog 2 Protects against Podocyte Oxidative Stress and Renal Injury in Diabetes

Enhancer of zeste homolog 2 depletion arrests the proliferation of hepatoblastoma cells

Alterations in enhancer of zeste homolog 2, matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression are associated with ex vivo and in vitro bone metastasis in renal cell carcinoma

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