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CBX4 acetoacetylation as an inhibitory mechanism of HIF-1α activity

文献类型：期刊论文

作者Li, Huiti8; Xu, Ying7; Zheng, Yimin6; Xue, Zian8; Li, Qingqing7; Jia, Xinglong4,5,8; Weng, Lietao7; Jiang, Lulu8; Ruan, Xiaoxue8; Zhang, Rong8
刊名CELL CHEMICAL BIOLOGY
出版日期2025-10-16
卷号32期号:10页码:21
ISSN号2451-9456
DOI10.1016/j.chembiol.2025.09.005
英文摘要HIF-1 alpha transcriptional activity is enhanced through SUMOylation mediated by CBX4. Despite the recognized importance of the CBX4-HIF-1 alpha axis, the molecular mechanisms governing its regulation remain largely unclear. In this study, phenotypic screening of a 101,254-compound library followed by structural optimization led to the identification of XZA-1, a small molecule capable of disrupting CBX4-mediated HIF-1 alpha transcriptional activation. Mechanistic investigations revealed that XZA-1 activates HADH, a key enzyme in fatty acid beta-oxidation, resulting in increased intracellular levels of acetoacetyl-CoA. This metabolite promotes acetoacetylation of CBX4 at lysine 106, thereby reducing its SUMO E3 ligase activity. In a CBX4-overexpressing xenograft model, XZA-1 demonstrated antitumor effects by enhancing CBX4 K106 acetoacetylation. Additionally, elevated levels of CBX4 K106 acetoacetylation were observed in clinical HCC tissues from patients with better overall survival. These findings suggest that acetoacetyl-CoA functions as a potential antitumor metabolite and establish a novel pharmacological approach for modulating HIF-1 alpha transcriptional activity in cancer.
WOS关键词METABOLIC-REGULATION ; GENE-EXPRESSION ; CELL ; CANCER ; PC2 ; HIF-1
资助项目National Facility for Protein Science in Shanghai (NFPS), Shanghai Advanced Research Institute, Chinese Academy of Science ; National Natural Science Foundation of China[92253303] ; National Natural Science Foundation of China[22077019] ; National Natural Science Foundation of China[22507022] ; National Natural Science Foundation of China[22225702] ; National Natural Science Foundation of China[82272703] ; Shanghai Municipal Committee of Science and Technology[21TQ016] ; Shanghai Municipal Committee of Science and Technology[21XD1420600] ; Innovative Research Team of High-level Local Universities in Shanghai[SHSMU-ZDCX20212700] ; Elite Youth Project of Natural Science Foundation of Fujian Province[2023J06056]
WOS研究方向Biochemistry & Molecular Biology
语种英语
WOS记录号WOS:001600683500001
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/319690]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Xu, Ying; Cai, Jiabin; Chen, Guoqiang; Zhou, Lu
作者单位1.Hainan Med Univ, Hainan Acad Med, Sch Basic Med, Key Lab Trop Translat Med,Minist Educ, Haikou 571199, Hainan, Peoples R China
2.Shanghai Jiao Tong Univ, Renji Hosp, State Key Lab Syst Med Canc, Sch Med, Shanghai 200025, Peoples R China
3.Chinese Acad Sci, Shanghai Adv Res Inst, Zhangjiang Lab, Natl Facil Prot Sci Shanghai, Shanghai 201210, Peoples R China
4.Tongji Univ, Shanghai Peoples Hosp 4, Translat Res Inst Brain & Brain Like Intelligence, Sch Med, Shanghai 200434, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Fudan Univ, Zhongshan Hosp, Shanghai Key Lab Organ Transplantat,Key Lab Carcin, Liver Canc Inst,Dept Liver Surg & Transplantat, Shanghai 200032, Peoples R China
7.Shanghai Jiao Tong Univ, Key Lab Cell Differentiat & Apoptosis Chinese, Minist Educ, Sch Med, Shanghai 200025, Peoples R China
8.Fudan Univ, Shanghai Peoples Hosp 5, Inst Metab & Integrat Biol IMIB, Sch Pharm,Sch Life Sci, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Li, Huiti,Xu, Ying,Zheng, Yimin,et al. CBX4 acetoacetylation as an inhibitory mechanism of HIF-1α activity[J]. CELL CHEMICAL BIOLOGY,2025,32(10):21.
APA Li, Huiti.,Xu, Ying.,Zheng, Yimin.,Xue, Zian.,Li, Qingqing.,...&Zhou, Lu.(2025).CBX4 acetoacetylation as an inhibitory mechanism of HIF-1α activity.CELL CHEMICAL BIOLOGY,32(10),21.
MLA Li, Huiti,et al."CBX4 acetoacetylation as an inhibitory mechanism of HIF-1α activity".CELL CHEMICAL BIOLOGY 32.10(2025):21.

入库方式： OAI收割

来源：上海药物研究所

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