2. Academic Validation
  3. Deficiency of BCAT2-mediated branched-chain amino acid catabolism promotes colorectal cancer development

Deficiency of BCAT2-mediated branched-chain amino acid catabolism promotes colorectal cancer development

  • Biochim Biophys Acta Mol Basis Dis. 2023 Nov 4;1870(2):166941. doi: 10.1016/j.bbadis.2023.166941.
Zi-Ran Kang 1,  Shanshan Jiang 1,  Ji-Xuan Han 1,  Yaqi Gao 1,  Yile Xie 1,  Jinxian Chen 2,  Qiang Liu 3,  Jun Yu 4,  Xin Zhao 5,  Jie Hong 1,  Haoyan Chen 1,  Ying-Xuan Chen 1,  Huimin Chen 6,  Jing-Yuan Fang 7
Affiliations

Affiliations

  • 1 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 2 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 3 Department of Pathology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
  • 5 CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • 6 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: huimin.chan@foxmail.com.
  • 7 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: jingyuanfang@sjtu.edu.cn.
PMID: 37926361 DOI: 10.1016/j.bbadis.2023.166941
Abstract

Objective: Branched-chain amino acid (BCAA) metabolism is involved in the development of colorectal Cancer (CRC); however, the underlying mechanism remains unclear. Therefore, this study investigates the role of BCAA metabolism in CRC progression.

Methods: Dietary BCAA was administered to both azoxymethane-induced and azoxymethane/dextran sodium sulfate-induced CRC mouse models. The expression of genes related to BCAA metabolism was determined using RNA Sequencing. Adjacent tissue samples, obtained from 58 patients with CRC, were subjected to quantitative Real-Time PCR and immunohistochemical analysis. Moreover, the suppressive role of branched-chain aminotransferase 2 (BCAT2) in cell proliferation, Apoptosis, and xenograft mouse models was investigated. Alterations in BCAAs and activation of downstream pathways were also assessed using metabolic analysis and western blotting.

Results: High levels of dietary BCAA intake promoted CRC tumorigenesis in chemical-induced CRC and xenograft mouse models. Both the mRNA and protein levels of BCAT2 were decreased in tumor tissues of patients with CRC compared to those in normal tissues. Proliferation assays and xenograft models confirmed the suppressive role of BCAT2 in CRC progression. Furthermore, the accumulation of BCAAs caused by BCAT2 deficiency facilitated the chronic activation of mTORC1, thereby mediating the oncogenic effect of BCAAs.

Conclusion: BCAT2 deficiency promotes CRC progression through inhibition of BCAAs metabolism and chronic activation of mTORC1.

Keywords

BCAT2; Branched-chain amino acid; Colorectal cancer; Diet.

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