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

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

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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 spe-cific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and pro-teasome 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)en-hances 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.

Cyclin D1SUMOylationMantle cell lymphomaArsenic trioxideSENP2Proteasome degradation

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

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Research Center for Computer-aided Drug Discovery,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen 518055,China

Faculty of Pharmaceutical Sciences,Shenzhen Institute of Advanced Technology,Shenzhen 518055,China

Oncology Department,Johns Hopkins University School of Medicine,Baltimore,MD 21205,USA

Division of Spine Surgery,the First Affiliated Hospital of Guangxi Medical University,Nanning 530021,China

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

Wenzhou Institute,University of Chinese Academy of Sciences,Wenzhou 325000,China

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

School of Medicine,Southern University of Science and Technology,Shenzhen 518055,China

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National Key Research and Development Program of ChinaNational Natural Science Foundation of China(NSFC)grantsNational Natural Science Foundation of China(NSFC)grantsNational Natural Science Foundation of China(NSFC)grantsNational Natural Science Foundation of China(NSFC)grantsSIAT Innovation Program for Excellent Young Researchers

2021YFB380080082030067821611603428225071017482302757

2024

10.1016/j.apsb.2024.03.013

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(7)