Targeting EZH1/2 induces cell cycle arrest and inhibits cell proliferation through reactivation of p57~(CDKN1C) and TP53INP1 in mantle cell lymphoma

【Author】

Wei Li;Chengfeng Bi;Yating Han;Tian Tian;Xianhuo Wang;Huijing Bao;Xiaoying Xu;Xuhan Zhang;Lu Liu;Weiwei Zhang;Hai Gao;Huaqing Wang;Huilai Zhang;Bin Meng;Xi Wang;Kai Fu;Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer;Department of Pathology, Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer;Department of Pathology and Microbiology, University of Nebraska Medical Center;Department of Cell Biology,School of Basic Medical Sciences, Tianjin Medical University;Department of Laboratory Sciences,Tianjin Medical University;Cancer Center, Tianjin Union Hospital;

【Institution】

Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer;Department of Pathology, Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer;Department of Pathology and Microbiology, University of Nebraska Medical Center;Department of Cell Biology,School of Basic Medical Sciences, Tianjin Medical University;Department of Laboratory Sciences,Tianjin Medical University;Cancer Center, Tianjin Union Hospital;

【Abstract】

Objective: To explore the effect of dysregulation of epigenetic regulator EZH1 and EZH2 on the proliferation in MCL and the underlying mechanisms.Methods: In this study, we elucidated the role of EZH1 and EZH2 overexpression by immunohistochemistry and correlated them to clinical outcome in 41 MCL patients.Quantitative real-time PCR and Western blot were applied to confirm the level of EZH1 and EZH2 in well-characterized MCL cell lines which were compared to those of na?ve B cells.Then we manipulated the expression of EZH1 and EZH2 in MCL cells using CRISPR/Cas9 system to directly investigate their functional roles in MCL.We also evaluated the effect of two small molecule selective inhibitors, EPZ005687 and UNC1999, on MCL cell proliferation, cell cycle distribution 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, the overexpression of EZH2 is associated with poor OS in the patients.Nevertheless, simple EZH2 depletion in vitro has little impact on the viability of MCL cells, predominantly because of the consequent up-regulation of EZH1.Consistently, UNC1999, a dual EZH1/2 inhibitor, unlike the EZH2 selective inhibitor EPZ005687, exerts a potent inhibitory effect on MCL cells.Furthermore, we discover CDKN1C and TP53 INP1 as the two important cell cycle regulators, the expression of which are repressed by EZH1/2 mediated 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 for prognosis prediction.The dual inhibition of EZH1/2 is a promising therapeutic strategy for MCL.

【Keywords】

Mantle cell lymphoma;;EZH1;;EZH2;;CRISPR/Cas9

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Total: 12 articles

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