Oncogenic histone methyltransferase EZH2: A novel prognostic marker with therapeutic potential in endometrial cancer

Oki, Sadaaki; Sone, Kenbun; Oda, Katsutoshi; Hamamoto, Ryuji; Ikemura, Masako; Maeda, Daichi; Takeuchi, Makoto; Tanikawa, Michihiro; Mori‐Uchino, Mayuyo; Nagasaka, Kazunori; Miyasaka, Aki; Kashiyama, Tomoko; Ikeda, Yuji; Arimoto, Takahide; Kuramoto, Hiroyuki; Wada-Hiraike, Osamu; Kawana, Kei; Fukayama, Masashi; Osuga, Yutaka; Fujii, Tomoyuki

doi:10.18632/oncotarget.16316

Cited by 58 publications

(42 citation statements)

References 42 publications

(47 reference statements)

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“…The expression of EZH2 in endometrial carcinoma tissue was not correlated with the menopausal status or age of the patients (P>0.05): however, it was correlated with histological grade, depth of tumor invasion, lymph node metastasis and TNM stage (P<0.05). These correlations are consistent with findings of other research studies ( 20 – 22 ).…”

Section: Discussionsupporting

confidence: 93%

Expression of EZH2 in endometrial carcinoma and its effects on proliferation and invasion of endometrial carcinoma cells

Zhang

Huai

2017

Oncol Lett

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Expression of enhancer of zeste homolog 2 (EZH2) has been implicated in cancer pathology, but research on its mechanistic activity is limited. The present study sought to assess the levels expression of EZH2 in patients with endometrial carcinoma (EC) and to explore the effects of EZH2 downregulation on the biological behavior of endometrial carcinoma RL-952 cells. Samples were obtained from a total of 104 patients with EC and an immunohistochemical assay was used to detect the expression of EZH2 in cancer and adjacent tissues. The relationship between the expression of EZH2 and the clinicopathological features was analyzed. Endometrial carcinoma RL-952 cells were transfected with chemically synthesized siRNA to conduct targeting inhibition of EZH2 expression. The expression levels of EZH2 protein were detected by immunoblotting. MTT and Transwell assays were used to detect the changes of cell proliferation and invasion after EZH2 downregulation. Of the 104 cases of endometrial carcinoma samples, 71 cases showed positive expression of EZH2, with an expression rate of 68.27%. In 104 cases of adjacent tissue samples, 25 cases showed positive expression of EZH2, with an expression rate of 24.03%. The expression of EZH2 in endometrial carcinoma tissue was significantly higher than that in adjacent tissue (P<0.05). The expression of EZH2 in endometrial carcinoma tissue was not correlated with the menopausal status and age of patients (P>0.05), but was correlated with the histological grade, depth of tumor invasion, lymph node metastasis and TNM stage (P<0.05). The expression of E2H2 was significantly downregulated by si-E2H2 and the proliferation and invasion abilities of cells were significantly reduced after EZH2 downregulation (P<0.05). EZH2 is closely related to the development of endometrial carcinoma and can enhance the proliferative activity of endometrial carcinoma RL-952 cells and promote cell invasion.

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Section: Discussionsupporting

confidence: 93%

Expression of EZH2 in endometrial carcinoma and its effects on proliferation and invasion of endometrial carcinoma cells

Zhang

Huai

2017

Oncol Lett

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“…As a common gynecological malignancy among women, endometrial cancer has the highest incidence in those between the ages of 55 and 65 years old ( 1 ). Currently, the incidence of endometrial cancer presents an increasing trend worldwide, which is mainly ascribed to the increasing incidence of obesity and nulliparity ( 2 ). In the majority of cases, a patient suffering from endometrial cancer is usually diagnosed at a relatively early stage, which profoundly benefits curing of the disease by surgical strategies ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of miR-183-5p is responsible for the promotion of apoptosis and inhibition of the epithelial-mesenchymal transition, proliferation, invasion and migration of human endometrial cancer cells by downregulating Ezrin

et al. 2018

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Endometrial cancer is a life-threatening malignancy that affects women all over the world, and it has an increasing incidence. MicroRNAs (miRNAs/miRs) have been reported to be involved in cellular activities in endometrial cancer. The present study aimed to examine the effects of miR-183-5p on the epithelial-mesenchymal transition (EMT), proliferation, invasion, migration and apoptosis of human endometrial cancer cells by targeting Ezrin. Primary endometrial cancer tissues and adjacent normal tissues were obtained for the investigation. The protein expression of Ezrin in tissues was detected by immunohistochemistry. The expression level of miR-183-5p and the mRNA and protein expression levels of Ezrin and EMT-associated genes were determined by reverse transcription-quantitative polymerase chain reaction and western blot analyses. Endometrial cancer cells were treated with miR-183-5p inhibitors, small interfering RNA targeting Ezrin or miR-183-5p inhibitors. Cell proliferation, cell cycle, apoptosis, migration and invasion were then evaluated using an MTT assay, flow cytometry, scratch test and Transwell assay, respectively. Compared with normal adjacent tissues, the expression of miR-183-5p was decreased in endometrial cancer tissues, and the expression of Ezrin was significantly increased in endometrial cancer tissues. The protein expression of Ezrin was correlated with the severity and poor prognosis of endometrial cancer. Notably, the target prediction program and the luciferase reporter gene assay confirmed that miR-183-5p targeted and negatively regulated the expression of Ezrin. In vivo experiments revealed that the increased expression of miR-183-5p and decreased expression of Ezrin inhibited EMT, cell proliferation, migration and invasion, but promoted cell apoptosis in Ishikawa cells. These results suggested that the upregulated expression of miR-183-5p promoted apoptosis and suppressed the EMT, proliferation, invasion and migration of human endometrial cancer cells by downregulating Ezrin.

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“…This study further identified EZH2 as an independent dismal predictor for overall survival, after accounting for known prognostic factors, such as age, race, tumor type, lymphovascular invasion, tumor grade, and clinical FIGO stage [16]. Another series of 104 endometrial cancer cases revealed that higher EZH2 protein expression was independently and significantly correlated with worse progression-free survival, but not with overall survival [17]. Findings from the above studies support that EZH2 functions as an oncogene and merits further preclinical investigation as a novel drug target in endometrial cancer.…”

Section: Endometrial Cancermentioning

confidence: 67%

Clinicopathologic significance of protein lysine methyltransferases in cancer

et al. 2020

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Protein lysine methyltransferases (PKMTs) constitute a large family of approximately 50 chromatin modifiers that mono-, di- and/or tri-methylate lysine residues on histone and non-histone substrates. With the advent of The Cancer Genome Atlas, it became apparent that this family of chromatin modifiers harbors frequent genetic and expression alterations in multiple types of cancer. In this regard, past and ongoing preclinical studies have provided insight into the mechanisms of action of some of these enzymes, laying the ground for the ongoing development of PKMT inhibitors as novel anticancer therapeutics. The purpose of this review is to summarize existing data obtained by different research groups through immunohistochemical analysis of the protein expression levels of PKMTs, and their respective clinicopathologic associations. We focused on studies that used immunohistochemistry to associate protein expression levels of specific PKMTs, as well as several established histone methylation marks, with clinicopathologic features and survival outcomes in various cancer types. We also review ongoing clinical trials of PKMT inhibitors in cancer treatment. This review underscores the clinical relevance and potential of targeting the family of PKMT enzymes as the next generation of cancer therapy.

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Oncogenic histone methyltransferase EZH2: A novel prognostic marker with therapeutic potential in endometrial cancer

Cited by 58 publications

References 42 publications

Expression of EZH2 in endometrial carcinoma and its effects on proliferation and invasion of endometrial carcinoma cells

Expression of EZH2 in endometrial carcinoma and its effects on proliferation and invasion of endometrial carcinoma cells

Upregulation of miR-183-5p is responsible for the promotion of apoptosis and inhibition of the epithelial-mesenchymal transition, proliferation, invasion and migration of human endometrial cancer cells by downregulating Ezrin

Clinicopathologic significance of protein lysine methyltransferases in cancer

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