Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment

Marchesi, Irene; Bagella, Luigi

doi:10.5306/wjco.v7.i2.135

Cited by 30 publications

(22 citation statements)

References 138 publications

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“…It has been found that the over expression of EZH2 leads to a number of cancer with elevated levels of EZH2 found in breast as well as prostate cancer patients. The elevated level of EZH2 may be attributed to the mutation of residues Y641 to a phenylalanine (Y641F) and A677 to a glycine (A677G) present in the SET domain, which increases the activity of trimethylation in the protein 1 2 .…”

mentioning

confidence: 99%

Structural insights into conformational stability of both wild-type and mutant EZH2 receptor

Aier

Varadwaj

Raj

2016

Sci Rep

253

115

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Polycomb group (PcG) proteins have been observed to maintain the pattern of histone by methylation of the histone tail responsible for the gene expression in various cellular processes, of which enhancer of zeste homolog 2 (EZH2) acts as tumor suppressor. Overexpression of EZH2 results in hyper activation found in a variety of cancer. Point mutation on two important residues were induced and the results were compared between the wild type and mutant EZH2. The mutation of Y641 and A677 present in the active region of the protein alters the interaction of the top ranked compound with the newly modeled binding groove of the SET domain, giving a GLIDE score of −12.26 kcal/mol, better than that of the wild type at −11.664 kcal/mol. In depth analysis were carried out for understanding the underlying molecular mechanism using techniques viz. molecular dynamics, principal component analysis, residue interaction network and free energy landscape analysis, which showed that the mutated residues changed the overall conformation of the system along with the residue-residue interaction network. The insight from this study could be of great relevance while designing new compounds for EZH2 enzyme inhibition and the effect of mutation on the overall binding mechanism of the system.

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mentioning

confidence: 99%

Structural insights into conformational stability of both wild-type and mutant EZH2 receptor

Aier

Varadwaj

Raj

2016

Sci Rep

253

115

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“…Overexpression of EZH2 has been found to be associated with tumor aggressiveness, metastasis, and poor prognosis in multiple cancers [17-20], including lung cancer [21, 22]. MiR-26a was documented to suppress tumor growth by targeting EZH2 in some tumors [23-25].…”

Section: Resultsmentioning

confidence: 99%

MiRNA-26a Contributes to the Acquisition of Malignant Behaviors of Doctaxel-Resistant Lung Adenocarcinoma Cells through Targeting EZH2

Chen

Tao

et al. 2017

Cell Physiol Biochem

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Background/Aims: Accumulating evidence revealed that microRNAs (miRNAs) have been demonstrated as critical molecules in tumor development and progression. MiR-26a, located in a fragile chromosomal region associated with various human cancer, has been reported to be involved in regulating various cellular process, such as proliferation, apoptosis and invasion through targeting multiple oncogene. Docetaxel-mediated chemotherapy has been applied in improving the survival and prognosis of patients with advanced lung adenocarcinoma (LAD). However, chemoresistance remains a major impediment to clinical application of this agent. It has been presented that decreased miR-26a expression lead to cisplatin resistance and promoted growth and migration in human lung cancer. Enhancer of zeste homolog 2 (EZH2) is the target of miR-26a. The present study aimed to investigate the function of miR-26a/EZH2 in the acquisition of malignant behaviors of LAD. Methods: MiR-26a and EZH2 expression levels in the dcetaxel-insensitive groups (n = 19) and the docetaxel-sensitive groups (n = 18) were assessed by qRT-PCR. Colony formation assay, flow cytometric analysis, wound healing assay, cell transwell assays and western blotting were performed to assess the effects of miR-26a on proliferation, apoptosis and epithelial-to-mesenchymal (EMT) phenotypes in docetaxel resistant LAD cells in vitro. Xenograft transplantation, immunohistochemistry, tunel assays and western blotting assays were employed to demonstrate the role of miR-26a in docetaxel resistant LAD cells in vivo. The expression level of EZH2 in docetaxel-resistant LAD cells and corresponding parental cells was detected by qRT-PCR and western blotting. The relationship between miR-26a and EZH2 was confirmed by luciferase reporter assay. And rescue assays were performed to further confirm that miRNA-26a contributes to the acquisition of malignant behaviors of docetaxel-resistant LAD cells through targeting EZH2. Results: MiR-26a was significantly down-regulated in the dcetaxel-insensitive groups (n = 19) compared with the docetaxel-sensitive groups (n = 18) assessed by qRT-PCR. MiR-26a decreased the proliferation, increased the apoptosis rate and reversed EMT to MET of docetaxel-resistant LAD cells both in vivo and vitro. EZH2 was confirmed as target of miR-26a. Rescue assays further verified that the function of miR-26a exerts in docetaxel-resistant LAD cells is through targeting EZH2. Conclusions: Our data revealed that overexpression of miR-26a in docetaxel-resistant LAD cells could decrease the proliferation, increase the apoptosis rate and reverse EMT to MET of docetaxel-resistant LAD cells both in vivo and vitro and such function is partially exerted via downregulating EZH2. MiR-26a/EZH2 signal pathway makes contribute to the malignant phenotype of docetaxel-resistant of LAD cells which indicated that miR-26a exerts pivotal functions in the molecular etiology of chemoresistant lung adenocarcinoma.

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“…RT is used as an adjuvant or neoadjuvant treatment in MPM, mainly in a palliative setting (8)(9)(10). As standard practice, patients undergoing an EPP receive adjuvant conventionally fractionated RT (50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60) in the ipsilateral hemithorax area (18,19). In node-negative MPM patients, neoadjuvant therapy, based on intensity-modulated RT (IMRT) consisting of a fractionated irradiation of 5-6 Gy, is delivered before EPP (20)(21)(22).…”

Section: Radiotherapymentioning

confidence: 99%

Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future

et al. 2020

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Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the pleural surface associated with asbestos exposure. The median survival of MPM patients is a mere 8-14 months, and there are few biomarkers and no cure available. It is hoped that, eventually, the incidence of MPM will drop and remain low and constant, given that most nations have banned the use of asbestos, but in the meantime, the incidence in Europe is still growing. The exact molecular mechanisms that explain the carcinogenicity of asbestos are not known. Standard therapeutic strategies for MPM include surgery, often coupled with chemotherapy and/or radiotherapy, in a small percentage of eligible patients and chemotherapy in tumors considered unresectable with or without adjuvant radiotherapy. In recent years, several new therapeutic avenues are being explored. These include angiogenesis inhibitors, synthetic lethal treatment, miRNA replacement, oncoviral therapies, and the fast-growing field of immunotherapy alone or in combination with chemotherapy. Of particular promise are the multiple options offered by immunotherapy: immune checkpoint inhibitors, tumor vaccines, and therapies taking advantage of tumor-specific antigens, such as specific therapeutic antibodies or advanced cell-based therapies exemplified by the CART cells. This review comprehensively presents both old and new therapeutic options in MPM, focusing on the results of the numerous recent and ongoing clinical trials in the field, including the latest data presented at international meetings (AACR, ASCO, and ESMO) this year, and concludes that more work has to be done in the framework of tailored therapies to identify reliable targets and novel biomarkers to impact MPM management.

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Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment

Cited by 30 publications

References 138 publications

Structural insights into conformational stability of both wild-type and mutant EZH2 receptor

Structural insights into conformational stability of both wild-type and mutant EZH2 receptor

MiRNA-26a Contributes to the Acquisition of Malignant Behaviors of Doctaxel-Resistant Lung Adenocarcinoma Cells through Targeting EZH2

Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future

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