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The Effect of Direct and Indirect EZH2 Inhibition in Rhabdomyosarcoma Cell Lines

Enhancer of Zeste homolog 2 (EZH2) is involved in epigenetic regulation of gene transcription by catalyzing trimethylation of histone 3 at lysine 27. In rhabdomyosarcoma (RMS), increased EZH2 protein levels are associated with poor prognosis and increased metastatic potential, suggesting EZH2 as a therapeutic target. The inhibition of EZH2 can be achieved by direct inhibition which targets only the enzyme activity or by indirect inhibition which also affects activities of other methyltransferases and reduces EZH2 protein abundance. We assessed the direct inhibition of EZH2 by EPZ005687 and the indirect inhibition by 3-deazaneplanocin (DZNep) and adenosine dialdehyde (AdOx) in the embryonal RD and the alveolar RH30 RMS cell line. EPZ005687 was more effective in reducing the cell viability and colony formation, in promoting apoptosis induction, and in arresting cells in the G1 phase of the cell cycle than the indirect inhibitors. DZNep was more effective in decreasing spheroid viability and size in both cell lines than EPZ005687 and AdOx. Both types of inhibitors reduced cell migration of RH30 cells but not of RD cells. The results show that direct and indirect inhibition of EZH2 affect cellular functions differently. The alveolar cell line RH30 is more sensitive to epigenetic intervention than the embryonal cell line RD.

 

Comments：

The information provided in your statement suggests that EZH2 is a potential therapeutic target in RMS. The study assessed the effectiveness of two types of inhibitors, direct and indirect, in reducing the viability and colony formation, promoting apoptosis induction, arresting cells in the G1 phase of the cell cycle, decreasing spheroid viability and size, and reducing cell migration in the embryonal RD and alveolar RH30 RMS cell lines.

The findings suggest that the direct inhibitor, EPZ005687, is more effective than the indirect inhibitors, DZNep and AdOx, in reducing the cell viability and colony formation, promoting apoptosis induction, and arresting cells in the G1 phase of the cell cycle. On the other hand, DZNep was more effective in decreasing spheroid viability and size in both cell lines than EPZ005687 and AdOx. Moreover, both types of inhibitors reduced cell migration of RH30 cells but not of RD cells.

The results suggest that direct and indirect inhibition of EZH2 affect cellular functions differently, and the alveolar cell line RH30 is more sensitive to epigenetic intervention than the embryonal cell line RD. These findings provide valuable information for developing new therapeutic strategies targeting EZH2 in RMS.

Related Products

Cat.No. Product Name Information
S7004 EPZ005687 EPZ005687 is a potent and selective inhibitor of EZH2 with Ki of 24 nM in a cell-free assay, 50-fold selectivity against EZH1 and 500-fold selectivity against 15 other protein methyltransferases.

Related Targets

Histone Methyltransferase EZH1/2