Targeting EZH1/2 induces cell cycle arrest and inhibits cell proliferation through reactivation of p57CDKN1C and TP53INP1 in mantle cell lymphoma.

Objective: To explore the effect of dysregulation of epigenetic regulator EZH1 and EZH2 on the proliferation in MCL and theunderlying mechanisms. Methods: In this study, we elucidated the role of EZH1 and EZH2 overexpression by immunohistochemistry and correlated themto clinical outcome in 41 MCL patients. Quantitative real-time PCR and Western blot were applied to confirm the level of EZH1and EZH2 in well-characterized MCL cell lines which were compared to those of naive B cells. Then we manipulated theexpression of EZH1 and EZH2 in MCL cells using CRISPR/Cas9 system to directly investigate their functional roles in MCL. Wealso evaluated the effect of two small molecule selective inhibitors, EPZ005687 and UNC1999, on MCL cell proliferation, cell cycledistribution and apoptosis in vitro. Finally, we performed RNA-sequencing (RNA-Seq) and Chromatin immunoprecipitation(ChIP) assay to further gain insight into the underlying molecular mechanisms. Results: We found that EZH2 protein is overexpressed in approximately half of this cohort of MCL cases. More importantly, theoverexpression of EZH2 is associated with poor OS in the patients. Nevertheless, simple EZH2 depletion in vitro has little impacton the viability of MCL cells, predominantly because of the consequent up-regulation of EZH1. Consistently, UNC1999, a dualEZH1/2 inhibitor, unlike the EZH2 selective inhibitor EPZ005687, exerts a potent inhibitory effect on MCL cells. Furthermore, wediscover CDKN1C and TP53INP1 as the two important cell cycle regulators, the expression of which are repressed by EZH1/2mediated epigenetic regulation and are restored by EZH1/2 dual inhibition. Conclusions: Our study suggests that EZH2 participates in the pathogenesis of MCL which may serve as a potential biomarker forprognosis prediction. The dual inhibition of EZH1/2 is a promising therapeutic strategy for MCL. Cite this article as: Li W, Bi C, Han Y, Tian T, Wang X, Bao H, et al.Targeting EZH1/2 induces cell cycle arrest and inhibits cell proliferationthrough reactivation of p57CDKN1C and TP53INP1 in mantle cell lymphoma.Cancer Biol Med. 2019; 16: 530-9. doi: 10.20892/j.issn.2095-3941.2018.0380