Enhanced BCAT1 activity and BCAA metabolism promotes RhoC activity in cancer progression

• Published in: Nature metabolism Vol. 5; no. 7; pp. 1159 - 1173
• Main Authors: Qian, Lin, Li, Na, Lu, Xiao-Chen, Xu, Midie, Liu, Ying, Li, Kaiyue, Zhang, Yi, Hu, Kewen, Qi, Yu-Ting, Yao, Jun, Wu, Ying-Li, Wen, Wenyu, Huang, Shenglin, Chen, Zheng-Jun, Yin, Miao, Lei, Qun-Ying
• Format: Journal Article
• Language: English
• Published: Germany Nature Publishing Group 01.07.2023
• Subjects: Amino acids; Cell adhesion & migration; Cell growth; Chromatography; Enzymatic activity; Enzyme kinetics; Gastric cancer; Genomes; Glioma; Glutamic acid; Leukemia; Metabolism; Metabolites; Metastases; Metastasis; Mutation; Pancreatic cancer; Phenotypes; Transaminase
• ISSN: 2522-5812
• DOI: 10.1038/s42255-023-00818-7

Increased expression of branched-chain amino acid transaminase 1 or 2 (BCAT1 and BCAT2) has been associated with aggressive phenotypes of different cancers. Here we identify a gain of function of BCAT1 glutamic acid to alanine mutation at codon 61 (BCAT1 ) enriched around 2.8% in clinical gastric cancer samples. We found that BCAT1 confers higher enzymatic activity to boost branched-chain amino acid (BCAA) catabolism, accelerate cell growth and motility and contribute to tumor development. BCAT1 directly interacts with RhoC, leading to elevation of RhoC activity. Notably, the BCAA-derived metabolite, branched-chain α-keto acid directly binds to the small GTPase protein RhoC and promotes its activity. BCAT1 knockout-suppressed cell motility could be rescued by expressing BCAT1 or adding branched-chain α-keto acid. We also identified that candesartan acts as an inhibitor of BCAT1 , thus repressing RhoC activity and cancer cell motility in vitro and preventing peritoneal metastasis in vivo. Our study reveals a link between BCAA metabolism and cell motility and proliferation through regulating RhoC activation, with potential therapeutic implications for cancers.