A non-metabolic function of hexokinase 2 in small cell lung cancer:promotes cancer cell stemness by increasing USP11-mediated CD133 stability
作者机构：Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Laboratory of Translational MedicineNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Department of Medical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Department of PathologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Central LaboratoryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital&Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenGuangdong 518116P.R.China Zhejiang Provincial Key Laboratory of Pancreatic DiseaseThe First Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhouZhejiang 310029P.R.China Cancer CenterZhejiang UniversityHangzhouZhejiang 310029P.R.China
出 版 物：《Cancer Communications》 (癌症通讯（英文）)
年 卷 期：2022年第42卷第10期
页 面：1008-1027页
核心收录：
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：Ministry of Science and Technology of the People’s Republic of China,Grant/Award Number:2020YFA0803300 National Natural Science Foundation of China,Grant/Award Numbers:82188102,82030074,82122053,32100574 Beijing Municipal Science&Technology Commission,Grant/Award Number:Z191100006619115 R&D Program of Beijing Municipal Education commission,Grant/Award Number:KJZD20191002302 CAMS Innovation Fund for Medical Science,Grant/Award Numbers:2021-1-I2M-012,2021-I2M-1-067 Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2021-PT310-001 Key-Area Research and Development Program of Guangdong Province,Grant/Award Number:2021B0101420005 Sanming Project of Medicine in Shenzhen,Grant/Award Numbers:SZSM201612097,SZSM201812062 Aiyou Foundation,Grant/Award Number:KY201701 Natural Science Foundation of Shandong Province,Grant/Award Number:ZR2020QH191 Zhejiang Natural Science Foundation-Key Project,Grant/Award Number:LD21H160003 Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang,Grant/Award Number:2019R01001 Zhimin Lu is the Kuancheng Wang Distinguished Chair。
主 题：HK2 metabolic enzyme non-metabolic function cancer stem-like cell CD133 USP11 ubiquitylation SCLC
摘 要：Background:Maintenance of cancer stem-like cell(CSC)stemness supported by aberrantly regulated cancer cell metabolism is critical for CSC self-renewal and tumor progression.As a key glycolytic enzyme,hexokinase 2(HK2)plays an instrumental role in aerobic glycolysis and tumor progression.However,whether HK2 directly contribute to CSC stemness maintenance in small cell lung cancer(SCLC)is largely unclear.In this study,we aimed to investgate whether HK2 independent of its glycolytic activity is directly involved in stemness maintenance of CSC in SCLC.Methods:Immunoblotting analyses were conducted to determine the expression of HK2 in SCLC CSCs and their differentiated counterparts.CSC-like properties and tumorigenesis of SCLC cells with or without HK2 depletion or overexpression were examined by sphere formation assay and xenograft mouse model.Immunoprecipitation and mass spectrometry analyses were performed to identify the binding proteins of CD133.The expression levels of CD133-associated and CSC-relevant proteins were evaluated by immunoblotting,immunoprecipitation,immunofluorescence,and immunohistochemistry assay.RNA expression levels of Nanog,POU5F1,Lin28,HK2,Prominin-1 were analyzed through quantitative reverse transcription PCR.Polyubiquitination of CD133 was examined by in vitro or in vivo ubiquitination assay.CD133+cells were sorted by flow cytometry using an anti-CD133 antibody.Results:We demonstrated that HK2 expression was much higher in CSCs of SCLC than in their differentiated counterparts.HK2 depletion inhibited CSC stemness and promoted CSC differentiation.Mechanistically,nonmitochondrial HK2 directly interacted with CD133 and enhanced CD133 expression without affecting CD133 mRNA levels.The interaction of HK2 and CD133 promoted the binding of the deubiquitinase ubiquitin-specific protease 11(USP11)to CD133,thereby inhibiting CD133 polyubiquitylation and degradation.HK2-mediated upregulation of CD133 expression enhanced the expression of cell renewal regulators,SCLC cell stemness,and tumor growth in mice.In addition,HK2 expression was positively correlated with CD133 expression in human SCLC specimens,and their expression levels were associated with poor prognosis of SCLC patients.Conclusions:These results revealed a critical non-metabolic function of HK2 in promotion of cancer cell stemness.Our findings provided new insights into the multifaceted roles of HK2 in tumor development.
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