2. Academic Validation
  3. CBX4 acetoacetylation as an inhibitory mechanism of HIF-1α activity

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

  • Cell Chem Biol. 2025 Oct 16;32(10):1249-1259.e9. doi: 10.1016/j.chembiol.2025.09.005.
Huiti Li 1,  Ying Xu 2,  Yimin Zheng 3,  Zian Xue 1,  Qingqing Li 4,  Xinglong Jia 5,  Lietao Weng 4,  Lulu Jiang 1,  Xiaoxue Ruan 1,  Rong Zhang 1,  Yue Yin 6,  Liying Zhou 1,  Fuyuan Li 1,  He Huang 1,  Jin Li 1,  Minjia Tan 7,  Jia Fan 3,  Jiabin Cai 8,  Guoqiang Chen 9,  Lu Zhou 10
Affiliations

Affiliations

  • 1 School of Pharmacy, Shanghai Fifth People's Hospital, School of Life Science, Institute of Metabolism & Integrative Biology (IMIB), Fudan University, Shanghai 201203, China.
  • 2 Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: yingxuxu@shsmu.edu.cn.
  • 3 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Shanghai 200032, China.
  • 4 Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 5 School of Pharmacy, Shanghai Fifth People's Hospital, School of Life Science, Institute of Metabolism & Integrative Biology (IMIB), Fudan University, Shanghai 201203, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.
  • 6 National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China.
  • 7 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 8 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Shanghai 200032, China. Electronic address: cai.jiabin@zs-hospital.sh.cn.
  • 9 Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Lab of Systems Medicine of Cancers, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine, Hainan Academy of Medicine, Hainan Medical University, Haikou 571199, Hainan, China. Electronic address: chengq@shsmu.edu.cn.
  • 10 School of Pharmacy, Shanghai Fifth People's Hospital, School of Life Science, Institute of Metabolism & Integrative Biology (IMIB), Fudan University, Shanghai 201203, China. Electronic address: zhoulu@fudan.edu.cn.
PMID: 41045931 DOI: 10.1016/j.chembiol.2025.09.005
Abstract

HIF-1α transcriptional activity is enhanced through SUMOylation mediated by CBX4. Despite the recognized importance of the CBX4-HIF-1α 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-1α transcriptional activation. Mechanistic investigations revealed that XZA-1 activates HADH, a key enzyme in fatty acid β-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-1α transcriptional activity in Cancer.

Keywords

CBX4; HADH; HIF-1α; cancer metabolism; lysine acetoacetylation.

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