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EZH2 inhibition synergies with CDK9 inhibition
H3K27me3.28 In our case, CDKI-73 did not change the EZH2 phosphorylation status. The elevated H3K27me3 is related to multiple factors, such as the amplification of EZH2 or another subunit of PRC2 and so on, in numerous tumor types.12 In addition, inactivation of UTX or JMJD3, resulting in the enrichment of H3K27me3, also has been detected in many kinds of cancers.32,33 In the present study, surprisingly, the expression of H3K27me3 increased while EZH2 decreased after treatment with CDKI- 73/Flavopiridol. Therefore, we paid more attention to the demethylases. Both the protein and mRNA levels of UTX and JMJD3 decreased earlier and more dramatically than EZH2, EED, and SUZ12 when exposed to CDK9i. Moreover, as expected, knock-down of CDK9 also elevat- ed H3K27me3 and decreased the level of JMJD3/UTX
more evidently than that of EZH2. Thus, we speculate that CDK9 inhibition reduced the expression of JMJD3/UTX more powerfully than that of EZH2, leading to H3K27me3 elevation. However, the detailed mecha- nism of upregulation of H3K27me3 by the loss of CDK9 still needs to be further explored.
In conclusion, we identified that the novel CDK9 inhibitor CDKI-73 exerts a potent anti-tumor activity against DLBCL both in vitro and in vivo, and represents an attractive therapeutic agent for DLBCL therapy. More importantly, EZH2i in combination with CDK9i results in a strong synergistic effect in DLBCL and other solid tumors by suppressing CDK9 inhibition-stimulated H3K27me3. These data provide a rational basis for the testing of CDK9i in combination with EZH2i in clinical trials.
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