Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression

• DOI: 10.1038/s41392-022-01248-9
• Publication Date: 2023-01-09T01:02:29Z
• Authors: Xiang-Peng Tan; Yan He; Jing Yang; Xian Wei; You-Long Fan; Guo-Geng Zhang; Yi-Dong Zhu; Zheng-Qiu Li; Hua-Xin Liao; Da-Jiang Qin; Xin-Yuan Guan; Bin Li
• Keywords: 0303 health sciences; Carcinoma, Hepatocellular; QH301-705.5; Liver Neoplasms; R; Myristic Acid; Article; 3. Good health; 03 medical and health sciences; Medicine; Humans; Biology (General); Protein Processing, Post-Translational

Abstract Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Identification underlying mechanism HCC progression and exploration new therapeutic drugs are urgently needed. Here, a compound library consisting 419 FDA-approved was taken to screen potential anticancer drugs. A series functional assays showed that desloratadine, an antiallergic drug, can repress proliferation in cell lines, cell-derived xenograft (CDX), patient-derived organoid (PDO) (PDX) models. N-myristoyl transferase 1 (NMT1) identified as target protein desloratadine by drug affinity responsive stability (DARTS) surface plasmon resonance (SPR) assays. Upregulation NMT1 expression enhanced but knockdown suppressed tumor growth vitro vivo. Metabolic labeling mass spectrometry analyses revealed Visinin-like 3 (VILIP3) substrate N-myristoylation modification, high or VILIP3 associated with advanced stages poor survival HCC. Mechanistically, binds Asn-246 inhibits its enzymatic activity, disrupting NMT1-mediated myristoylation subsequent NFκB/Bcl-2 signaling. Conclusively, this study demonstrates may be novel contributes biomarker