Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer

Song, Xian‐Rong; Gao, Tiantao; Wang, Ningyu; Feng, Qiang; You, Xinyu; Ye, Tinghong; Lei, Qian; Zhu, Yiping; Xiong, Menghua; Xia, Yong; Yang, Fangfang; Shi, Yu; Wei, Yuquan; Zhang, Lidan; Yu, Luoting

doi:10.1038/srep20864

Cited by 49 publications

(50 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With more and more research available, the epigenetic molecule EZH2 is regarded as a transcriptional repressor associated with many cancer types [14,15,16,17]. Our previous study demonstrated that compared to normal tissues, colorectal cancer tissues expressed higher levels of EZH2.…”

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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…46 Again, on the basis of 6 , ZLD1039 ( 10 ), which is 12-fold selective for EZH2 over EZH1, has been discovered. 47,48 Most recently, compound 11 , a potent EZH2 inhibitor, was cocrystallized with the active Ac /human PRC2 complex. 14 …”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Studies for Enhancer of Zeste Homologue 2 (EZH2) and Enhancer of Zeste Homologue 1 (EZH1) Inhibitors

Yang

Konze

et al. 2016

J. Med. Chem.

View full text Add to dashboard Cite

EZH2 or EZH1 (enhancer of zeste homologue 2 or 1) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 lysine 27 (H3K27). PRC2 hyperactivity and/or hypertrimethylation of H3K27 are associated with numerous human cancers, therefore inhibition of PRC2 complex has emerged as a promising therapeutic approach. Recent studies have shown that EZH2 and EZH1 are not functionally redundant and inhibition of both EZH2 and EZH1 is necessary to block the progression of certain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias. Despite the significant advances in discovery of EZH2 inhibitors, there has not been a systematic structure-activity relationship (SAR) study to investigate the selectivity between EZH2 and EZH1 inhibition. Here, we report our SAR studies that focus on modifications to various regions of the EZH2/1 inhibitor UNC1999 (5) to investigate the impact of the structural changes on EZH2 and EZH1 inhibition and selectivity.

show abstract

“…EZH2 overexpression has been identified in NPC, non-small cell lung cancer, chronic lymphocytic leukemia and breast cancer (15)(16)(17). Collectively, these studies suggest that EZH2 is a novel target oncogene and pharmacological inhibition of EZH2 may be therapeutic for certain types of cancer.…”

Section: Discussionmentioning

confidence: 93%

Efficacy of extracts of Celastrusï¿½orbiculatus in suppressing migration and invasion by inhibiting the EZH2/ROCK1 signaling pathway in human nasopharyngeal carcinoma

et al. 2018

View full text Add to dashboard Cite

Abstract. Celastrus orbiculatus extract (COE) has been used in folk medicine in China for the treatment of a number of diseases. In the laboratory, COE exhibits a variety of anticancer functions, including inhibition of metastasis. However, the underlying molecular anti-metastatic mechanism in nasopharyngeal carcinoma (NPC) cells remains unclear. The aim of the present study was to determine whether the anti-metastatic effect of COE was involved in inhibiting migration and invasion of human NPC cells. In vitro, cell viability and apoptosis of 5-8F cells were analyzed using an MTS assay and flow cytometry, respectively. Invasion and migration of 5-8F cells were analyzed using a Transwell assay. Protein and mRNA expression levels of 5-8F cells were analyzed by western blot analysis and the reverse transcription-quantitative polymerase chain reaction, respectively. COE significantly decreased cell viability in 5-8F cells and inhibited enhancer of zeste homolog 2 (EZH2) and Rho-associated coiled coil-containing protein kinase 1 (ROCK1) expression at the mRNA and protein levels. Furthermore, COE decreased the migration and invasion of 5-8F cells in a dose-dependent manner. The results of the present study suggested that COE prevents migration and invasion by suppressing the EZH2/ROCK1 signaling pathway in NPC cells. On the basis of the results of the present study, COE may be a novel anticancer agent for the treatment of metastasis in NPC.

show abstract

Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer

Cited by 49 publications

References 44 publications

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

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

Structure–Activity Relationship Studies for Enhancer of Zeste Homologue 2 (EZH2) and Enhancer of Zeste Homologue 1 (EZH1) Inhibitors

Efficacy of extracts of Celastrusï¿½orbiculatus in suppressing migration and invasion by inhibiting the EZH2/ROCK1 signaling pathway in human nasopharyngeal carcinoma

Contact Info

Product

Resources

About