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 ca...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.展开更多
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).
文摘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.
