OXCT1 regulates NF-κB signaling pathway through β-hydroxybutyrate-mediated ketone body homeostasis in lung cancer

作     者：Zhuo Lu Tianyu Han Tao Wang Mingxi Gan Caifeng Xie Bentong Yu Jian-Bin Wang Zhuo Lu;Tianyu Han;Tao Wang;Mingxi Gan;Caifeng Xie;Bentong Yu;Jian-Bin Wang

作者机构：College of Life ScienceNanchang UniversityNanchangJiangxi 330031China School of Basic Medical SciencesNanchang UniversityNanchangJiangxi 330031China Jiangxi Institute of Respiratory DiseaseThe First Affiliated Hospital of Nanchang UniversityNanchangJiangxi 330006China Department of Thoracic SurgeryThe First Affiliated Hospital of Nanchang UniversityNanchangJiangxi 330006China 

出 版 物：《Genes & Diseases》 (基因与疾病（英文）)

年 卷 期：2023年第10卷第2期

页      面：352-355页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by grants to Jian-Bin Wang,Caifeng Xie and Tianyu Han from the National Natural Science Foundation of China(No.82030086,81874043,82002761,and 81902346) Natural Science Foundation of Jiangxi Province(No.20192BAB215038,and 20192ACB20024) Major Discipline Academic and Technical Leaders Training Program of Jiangxi Province(No.20204BCJ23023). 

主　　题：homeostasis lung ketone 

摘      要：Metabolic reprogramming is one of the hallmarks of cancer.1 Ketone bodies behave as alternative fuel for cancer cells to support survival and proliferation.2 3-Oxoacid CoA-transferase 1 (OXCT1) is a key enzyme that catalyzes the first and rate-limiting step of ketolysis. Recently, several studies have revealed the significance of OXCT1 in cancer development, though the underlying mechanisms remain largely unknown.3 In this study, we revealed a novel regulatory mechanism for tumorigenesis that OXCT1 regulated SREBP1-TRIM21-p65 axis through ketone body homeostasis in non-small cell lung cancer (NSCLC). In terms of mechanism, we found that OXCT1 could activate NF-κB signaling pathway by suppressing transcriptional activity of the sterol regulatory element binding protein 1 (SREBP1). As a transcription factor, SREBP1 could bind to the promoter of E3 ubiquitin ligase TRIM21, which mediated the ubiquitination of p65. Furthermore, we demonstrated that OXCT1 could maintain the homeostasis of β-hydroxybutyrate (β-HB), which acted as a signaling metabolite to activate SREBP1. Thus, β-HB connected OXCT1 with SREBP1 to activate NF-κB signaling pathway and promoted tumor initiation and progression. Taken together, these findings highlight a previously unappreciated mechanism for activation of NF-κB signaling by OXCT1 and ketone body, and demonstrate that targeting OXCT1 can inhibit NSCLC tumorigenesis.