Disruption of cyclin D1 degradation leads to the development of mantle cell lymphoma  

作　　者：Ke Lu Ming Zhang Hongyu Qin Siyu Shen Haiqing Song Hua Jiang Chunxiang Zhang Guozhi Xiao Liping Tong Qing Jiang Di Chen 

机构地区：[1]Research Center for Computer-aided Drug Discovery,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen 518055,China [2]Faculty of Pharmaceutical Sciences,Shenzhen Institute of Advanced Technology,Shenzhen 518055,China [3]Oncology Department,Johns Hopkins University School of Medicine,Baltimore,MD 21205,USA [4]Division of Spine Surgery,the First Affiliated Hospital of Guangxi Medical University,Nanning 530021,China [5]Division of Sports Medicine and Adult Reconstructive Surgery,Department of Orthopedic Surgery,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,Nanjing 210008,China [6]Wenzhou Institute,University of Chinese Academy of Sciences,Wenzhou 325000,China [7]Department of Cardiology,Basic Medicine Innovation Center for Cardiometabolic Diseases of Ministry of Education,Institute of Cardiovascular Research,the Affiliated Hospital,Southwest Medical University,Luzhou 646000,China [8]School of Medicine,Southern University of Science and Technology,Shenzhen 518055,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第7期2977-2991,共15页药学学报（英文版）

基　　金：supported by National Key Research and Development Program of China(2021YFB3800800)to Di Chen and Liping Tong;supported by the National Natural Science Foundation of China(NSFC)grants(82030067,82161160342 and 82250710174)to Di Chen;grant(82302757)to Ke Lu;supported by SIAT Innovation Program for Excellent Young Researchers.

摘　　要：Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers.Here,we demonstrated that cyclin D1 is SUMOylated,and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1.We generated cyclin D1 mutant mice with mutations in the SUMOylation site,phosphorylation site,or both sites of cyclin D1,and found that double mutant mice developed a Mantle cell lymphoma(MCL)-like phenotype.We showed that arsenic trioxide(ATO)enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes,leading to MCL cell apoptosis.Treatment of severe combined immunodeficiency(SCID)mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth.In this study,we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.

关 键 词：Cyclin D1 SUMOYLATION Mantle cell lymphoma Arsenic trioxide SENP2 Proteasome degradation 

分 类 号：R733.4[医药卫生—肿瘤]