Derepression of the USP22-FASN axis by p53 loss under oxidative stress drives lipogenesis and tumorigenesis

• DOI: 10.1038/s41420-022-01241-9
• Publication Date: 2022-11-04T20:18:44Z
• Authors: Zelong Han; Ming Liu; Yuxin Xie; Kunlin Zeng; Ziling Zhan; Yanwen Chen; Li Wang; Xiaoxia Chen; Yaxin Luo; Yu Zeng; Hongchao Zhan; Yingzhuo Lin; Keqin Zhang; Xiaoxia Zhu; Side Liu; Xiaobei Luo; Aidong Zhou
• Keywords: 0301 basic medicine; 03 medical and health sciences; QH573-671; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Cytology; RC254-282; Article; 3. Good health

AbstractOverproduction of reactive oxygen species (ROS) and aberrant lipid metabolism are established hallmarks of cancer; however, the role of ROS in lipid synthesis during tumorigenesis is almost unknown. Herein, we show that ROS regulates lipid synthesis and thus controls colorectal tumorigenesis through a p53-dependent mechanism. In p53 wild-type colorectal cancer (CRC) cells, hydrogen peroxide (H2O2)-induced p53 expression represses the transcription of deubiquitinase USP22, which otherwise deubiquitinates and stabilizes Fatty Acid Synthase (FASN), and thus inhibits fatty acid synthesis. Whereas, in p53-deficient CRC cells, ROS-mediated inhibition of USP22 is relieved, leading to FASN stabilization, which thus promotes lipid synthesis and tumor growth. In human CRC specimens, USP22 expression is positively correlated with FASN expression. Our study demonstrates that ROS critically regulates lipid synthesis and tumorigenesis through the USP22-FASN axis in a p53-dependent manner, and targeting the USP22-FASN axis may represent a potential strategy for the treatment of colorectal cancer.