The novel EZH2 inhibitor, GSK126, suppresses cell migration and angiogenesis via down-regulating VEGF-A

Chen, Yatian; Zhu, Feng; Lin, Wei-Ren; Ying, Rongbiao; Yang, Yanmei; Zeng, Ling‐Hui

doi:10.1007/s00280-016-2990-1

Cited by 59 publications

(35 citation statements)

References 29 publications

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“…These results indicate that combined administration of a small-molecule EZH2 inhibitor such as GSK126 with conventional chemotherapy could be a new strategy for effective treatment of endometrial cancer. Several in vivo studies evaluating the use of GSK126 against various types of cancer cells in xenograft mouse models suggest its efficacy and feasibility [30, 33, 34]. In addition, a phase I clinical trial of GSK126 for patients with relapsed-refractory, diffuse large B-cell lymphoma and transformed follicular lymphoma has already started in the United States (ClinicalTrials.gov identifier: NCT02082977).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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The histone methyltransferase EZH2, a key epigenetic modifier, is known to be associated with human tumorigenesis. However, the physiological importance of EZH2 and its clinical relevance in endometrial cancer remain unclear. Hence, in the present study, we investigated the expression and function of EZH2 in endometrial cancer. In a quantitative real-time PCR analysis of 11 endometrial cancer cell lines and 52 clinical endometrial cancer specimens, EZH2 was significantly overexpressed in cancer cells and tissues compared to that in corresponding normal control cells and tissues. Kaplan-Meier survival analysis using data of the TCGA RNA-seq database and tissue microarrays (TMAs) indicated that EZH2 overexpression is associated with endometrial cancer prognosis. In addition, knockdown of EZH2 using specific siRNAs resulted in growth suppression and apoptosis induction of endometrial cancer cells, accompanied by attenuation of H3K27 trimethylation. Consistent with these results, treatment with GSK126, a specific EZH2 inhibitor, suppressed endometrial cancer cell growth and decreased the number of cancer cell colonies. Furthermore, GSK126 showed additive effects with doxorubicin or cisplatin, which are conventional drugs for treatment of endometrial cancer. Further studies should explore the therapeutic potential of inhibiting EZH2 in patients with endometrial cancer.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Thus, more research should be undertaken to get a better understanding of epigenetic mechanisms and the influence of EZH2 targeted agents on potential survival benefit in CRC patients, which may promote a novel clinical strategy for CRC treatment. Meanwhile, a variety of inhibitors suppress the EZH2 via different mechanisms, such as regulation of other targets or signal pathways, competing toward the SET domain of EZH2 and inducing relevant protein degradation [43,44,45]. All methods of inhibiting EZH2 seem have a potential benefit for treating solid tumors [45,46,47,48].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Enhancer of Zeste Homolog 2 (EZH2) is essential for the Induction of Autophagy and Apoptosis in Colorectal Cancer Cells

Yao

Yang

et al. 2016

Genes

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Increasing evidence indicates that elevated expression of enhancer of zeste homolog 2 gene (EZH2) in many human malignant tumors acts a significant role in the oncogenic process. However, the underlying molecular mechanism is still unclarified. It is evident that apoptosis and autophagy of tumor cells is crucial for the tumorigenesis and progression of cancer, however, the exact role of EZH2 plays in apoptosis and autophagy has not been fully elucidated in colorectal cancer (CRC). Our previous study found that the expression level of EZH2 was higher in CRC tumor tissues than in the paired normal tissues using immunohistochemical analysis. We also recently found that the autophagy-related gene-related protein Ambra1 plays an important role in the autophagy pathway in CRC cells. In this study, mRNA and protein expression of EZH2 in four CRC cell lines were tested at first and RKO and HCT116 cells showed the highest levels among them. Here we transfected with EZH2-shRNA, or added DZNep (an EZH2 inhibitor) to RKO and HCT116 cells in order to detect the effect of EZH2 on autophagy via determining the change of the protein expression of LC3 and Ambra1. The outcome indicated an obvious decrease of autophagy level in cells transfected with EZH2-shRNA or DZNep. We also found the apoptotic rate of cells was elevated significantly after downregulation of EZH2. In addition, compared to control group, CRC cells transfected with EZH2-shRNA or added DZNep revealed a significantly increased G1 cell cycle rate and an obvious decrease in the G2 cell cycle rate. Further analysis showed that knockdown of EZH2 induced cell-cycle arrest in CRC cells. Meanwhile, downregulation of EZH2 in CRC cells induces autophagy and apoptosis. Taken together, our results suggest that EZH2 plays a critical role in autophagy and apoptosis in the progression of CRC, which potentially facilitates the development of an ideal strategy for combating colorectal cancer.

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“…Regulation of angiogenesis by altering the expression of VEGF and its receptors may be a potential strategy to promote the repair of WMI. GSK126, a novel EZH2 inhibitor, inhibits cell migration and angiogenesis by downregulating VEGF‐A . Human NSCs promote vascular regeneration, neuroprotection, and functional recovery in mice with stroke by VEGF overexpression .…”

Section: Repair or Recovery Mechanism And Strategymentioning

confidence: 99%

“…GSK126, a novel EZH2 inhibitor, inhibits cell migration and angiogenesis by downregulating VEGF-A. 83 Human NSCs promote vascular regeneration, neuroprotection, and functional recovery in mice with stroke by VEGF overexpression. 84…”

Section: Angiogenesismentioning

confidence: 99%

White matter repair and treatment strategy after intracerebral hemorrhage

et al. 2019

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The predilection site of intracerebral hemorrhage (ICH) is in the basal ganglia, which is rich in white matter (WM) fiber bundles, such as cerebrospinal tract in the internal capsule. ICH induced damage to this area can easily lead to severe neurological dysfunction and affects the prognosis and quality of life of patients. At present, the pathophysiological mechanisms of white matter injury (WMI) after ICH have attracted researchers' attention, but studies on the repair and recovery mechanisms and therapy strategies remain rare. In this review, we mainly summarized the WM recovery and treatment strategies after ICH by updating the WMI‐related content by reviewing the latest researches and proposing the bottleneck of the current research.

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The novel EZH2 inhibitor, GSK126, suppresses cell migration and angiogenesis via down-regulating VEGF-A

Abstract: GSK126 inhibits cell migration and angiogenesis in solid tumor cell lines through down-regulation of VEGF-A expression. Thus, it may be considered as a novel anticancer drug candidate for solid tumor.

Cited by 59 publications

References 29 publications

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

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

Downregulation of Enhancer of Zeste Homolog 2 (EZH2) is essential for the Induction of Autophagy and Apoptosis in Colorectal Cancer Cells

White matter repair and treatment strategy after intracerebral hemorrhage

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