EZH2 inhibition induces senescence via ERK1/2 signaling pathway in multiple myeloma  

作　　者：Shushan Guo Qiongwei Tang Xuejie Gao Liangning Hu Ke Hu Hui Zhang Qikai Zhang Yue Lai Yujie Liu Zhuning Wang Shuaikang Chang Yifei Zhang Huifang Hu Dong An Yu Peng Haiyan Cai Jumei Shi 

机构地区：[1]Shanghai Clinical College,Anhui Medical University,Shanghai 200072,China [2]Department of Hematology,Shanghai East Hospital,Tongji University School of Medicine,Shanghai 200120,China [3]The Fifth Clinical Medical College of Anhui Medical University,Hefei 230022,China [4]Department of Hematology,Sir Run Run Shaw Hospital,Zhejiang University,Hangzhou 310016,China

出　　处：《Acta Biochimica et Biophysica Sinica》2024年第7期1055-1064,共10页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the National Natural Science Foundation of China(Nos.82350101 and 82170200 to J.S.,82100202 to L.H.,82170201 to Y.P.).

摘　　要：Epigenetic modifications play an important role in cellular senescence,and enhancer of zeste homolog 2(EZH2)is a key methyltransferase involved in epigenetic remodeling in multiple myeloma(MM)cells.We have previously demonstrated that GSK126,a specific EZH2 inhibitor,exhibits anti-MM therapeutic efficacy and safety in vivo and in vitro;however,its specific mechanism remains unclear.This study shows that GSK126 induces cellular senescence in MM,which is characterized by the accumulation of senescence-associated heterochromatin foci(SAHF)and p21,and increased senescence-associatedβgalactosidase activity.Furthermore,EZH2 is inhibited in ribonucleotide reductase regulatory subunit M2(RRM2)-overexpressing OCI-MY5 and RPMI-8226 cells.RRM2 overexpression inhibits the methyltransferase function of EZH2 and promotes its degradation through the ubiquitin-proteasome pathway,thereby inducing cellular senescence.In this senescence model,Lamin B1,a key component of the nuclear envelope and a marker of senescence,does not decrease but instead undergoes aberrant accumulation.Meanwhile,phosphorylation of extracellular signal-regulated protein kinase(ERK1/2)is significantly increased.The inhibition of ERK1/2 phosphorylation in turn partially restores Lamin B1 level and alleviates senescence.These findings suggest that EZH2 inhibition increases Lamin B1 level and induces senescence by promoting ERK1/2 phosphorylation.These data indicate that EZH2 plays an important role in MM cellular senescence and provide insights into the relationships among Lamin B1,p-ERK1/2,and cellular senescence.

关 键 词：multiple myeloma EZH2 Lamin B1 RRM2 cellular senescence 

分 类 号：R73[医药卫生—肿瘤]