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S. Xie et al.
small sets of cancers indeed benefited from EZH2-targeted therapies. Therefore, this study may also open opportuni- ties for EZH2i in solid tumor.
Keeping in mind the important role of the methylation of H3K27 in tumor progression, we also tried to explore the detailed mechanism stimulating H3K27me3 by CDKI- 73. In some studies CDK has been linked to H3K27
methylation. CDK1 and CDK2 have been reported to phosphorylate EZH2 at Thr350 and it is considered to be essential for the maintenance of H3K27me3 marks through cell division.27 Additionally, Thr487 is another residue of EZH2 that can be phosphorylated through acti- vation of CDK1, disrupting EZH2 binding with other PRC2 components, thereby resulting in a decline of
A
B
CDE
FG
Figure 6. The combined effect of CDK9 and EZH2i in multiple solid tumors. (A) The average combination index (CI) values. SGC-7901, MCF-7, MDA-MB-453 and SW620 cells were treated as mentioned in Figure 4D. (B) The combination of CDKI-73 and EZH2i inhibited MCF-7 and SGC-7901 colony formation. (C-D) Quantitative assessment of apoptosis and the expression of apoptosis-related proteins, H3K27me3 and γ-H2AX in MCF-7 and SW620 cells pretreated with EPZ6438/GSK126 for 48 hours (h) and then in combination with CDKI-73 for additional 24 h. (E) H3K27me3, and its related methyltransferases and demethylases level in MCF-7 and MDA-MB-453 cells after siCDK9. (F) Relative tumor volume (RTV) and average body weight of nude mice treated with 50 mg/kg CDKI-73 and 50 mg/kg EPZ66438 alone or together with inoculated SW620 cells. Data are expressed as the mean + standard error of the mean (SEM). (G) H3K27me3 and apoptosis-related proteins level in SW620 xenografts at the end of the in vivo experiment. C: CDKI-73; E: EPZ6438; G: GSK126. All data are representative of at least three independent exper- iments. ***P<0.001, **P<0.01, *P<0.05.
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