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

Lin Qian; Na Li; Xiao-Chen Lu; Midie Xu; Ying Liu; Kaiyue Li; Yi Zhang; Kewen Hu; Yu-Ting Qi; Jun Yao; Ying-Li Wu; Wenyu Wen; Shenglin Huang; Zheng-Jun Chen; Miao Yin; Qun-Ying Lei

doi:10.1038/s42255-023-00818-7

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

Nat Metab. 2023 Jul;5(7):1159-1173. doi: 10.1038/s42255-023-00818-7. Epub 2023 Jun 19.

Authors

Lin Qian^#^{1

2}, Na Li^#^{1

2

3}, Xiao-Chen Lu^#^{1

2}, Midie Xu^#^{1

4}, Ying Liu⁵, Kaiyue Li^{1

2}, Yi Zhang^{1

2}, Kewen Hu^{1

2}, Yu-Ting Qi^{1

2}, Jun Yao⁶, Ying-Li Wu⁷, Wenyu Wen^{1

8}, Shenglin Huang^{1

2}, Zheng-Jun Chen⁹, Miao Yin^{1

2}, Qun-Ying Lei^{10

11

12}

Affiliations

¹ Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; School of Basic Medical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Radiation Oncology; The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Department of Pathology, Fudan University Shanghai Cancer Center; Institute of Pathology, Fudan University, Shanghai, China.
⁵ Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁶ Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁷ Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁸ State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
⁹ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
¹⁰ Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; School of Basic Medical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Radiation Oncology; The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China. qlei@fudan.edu.cn.
¹¹ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. qlei@fudan.edu.cn.
¹² State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. qlei@fudan.edu.cn.

^# Contributed equally.

PMID: 37337119
DOI: 10.1038/s42255-023-00818-7

Abstract

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^E61A) enriched around 2.8% in clinical gastric cancer samples. We found that BCAT1^E61A 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^E61A or adding branched-chain α-keto acid. We also identified that candesartan acts as an inhibitor of BCAT1^E61A, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids, Branched-Chain / metabolism
Cell Proliferation
Humans
Keto Acids / metabolism
Neoplasms*
Proteins
Transaminases / metabolism

Substances

Proteins
Keto Acids
Amino Acids, Branched-Chain
Transaminases
BCAT1 protein, human