EZH2 inhibitors abrogate upregulation of trimethylation of H3K27 by CDK9 inhibitors and potentiate its activity against diffuse large B-cell lymphoma

Aberrant expression of CDK9/cyclin T1 has been found in diffuse large B-cell lymphoma, and suggest that CDK9 seems to be a potential therapeutic target for diffuse large B-cell lymphoma. Here, we firstly demonstrated that CDKI-73, a novel CDK inhibitor, potently blocks CDK9, triggered apoptosis and dramatically repressed diffuse large B-cell lymphoma cell growth owing to CDK9 inhibition. CDK9 inhibitors specifically elevated the trimethylation of H3K27, which we speculate was due to reduced expression of JMJD3/UTX. Considering the important role of the trimethylation of H3K27 in tumor progression, the synergistic effect of the combination therapy of CDK9 inhibitors with EZH2 inhibitors was investigated. EZH2 inhibitors reversed the upregulation of trimethylation of H3K27, and synergistically inhibited diffuse large B-cell lymphoma and other solid tumors growth in vitro and in vivo. These findings provide a rational basis for the application of CDK9 inhibitors in combination with EZH2 inhibitors in clinical trials.