2. Academic Validation
  3. CPT1A loss disrupts BCAA metabolism to confer therapeutic vulnerability in TP53-mutated liver cancer

CPT1A loss disrupts BCAA metabolism to confer therapeutic vulnerability in TP53-mutated liver cancer

  • Cancer Lett. 2024 Jul 28:595:217006. doi: 10.1016/j.canlet.2024.217006.
Yanfeng Liu 1,  Fan Wang 2,  Guoquan Yan 3,  Yu Tong 2,  Wenyun Guo 2,  Songling Li 4,  Yifei Qian 2,  Qianyu Li 5,  Yu Shu 2,  Lei Zhang 6,  Yonglong Zhang 7,  Qiang Xia 8
Affiliations

Affiliations

  • 1 Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China; Shanghai Institute of Transplantation, Shanghai, China. Electronic address: lyf7858188@163.com.
  • 2 State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
  • 4 School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
  • 5 Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: threebigrock@163.com.
  • 7 Central Laboratory, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China. Electronic address: yonglongzhang@126.com.
  • 8 Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China; Shanghai Institute of Transplantation, Shanghai, China. Electronic address: xiaqiang@shsmu.edu.cn.
PMID: 38823763 DOI: 10.1016/j.canlet.2024.217006
Abstract

Driver genomic mutations in tumors define specific molecular subtypes that display distinct malignancy competence, therapeutic resistance and clinical outcome. Although TP53 mutation has been identified as the most common mutation in hepatocellular carcinoma (HCC), current understanding on the biological traits and therapeutic strategies of this subtype has been largely unknown. Here, we reveal that fatty acid β oxidation (FAO) is remarkable repressed in TP53 mutant HCC and which links to poor prognosis in HCC patients. We further demonstrate that carnitine palmitoyltransferase 1 (CPT1A), the rate-limiting Enzyme of FAO, is universally downregulated in liver tumor tissues, and which correlates with poor prognosis in HCC and promotes HCC progression in the de novo liver tumor and xenograft tumor models. Mechanically, hepatic Cpt1a loss disrupts lipid metabolism and acetyl-CoA production. Such reduction in acetyl-CoA reduced histone acetylation and epigenetically reprograms branched-chain Amino acids (BCAA) catabolism, and leads to the accumulation of cellular BCAAs and hyperactivation of mTOR signaling. Importantly, we reveal that genetic ablation of CPT1A renders TP53 mutant liver Cancer mTOR-addicted and sensitivity to mTOR Inhibitor AZD-8055 treatment. Consistently, Cpt1a loss in HCC directs tumor cell therapeutic response to AZD-8055. CONCLUSION: Our results show genetic evidence for CPT1A as a metabolic tumor suppressor in HCC and provide a therapeutic approach for TP53 mutant HCC patients.

Keywords

BCAA metabolism; CPT1A; Fatty acid β oxidation; Hepatocellular carcinoma; TP53 mutant.

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