NAT10 inhibition promotes ac4C‐dependent ferroptosis to counteract sorafenib resistance in nasopharyngeal carcinoma

• Published in: Cancer science Vol. 115; no. 10; pp. 3256 - 3272
• Main Authors: Xue, Ziyi, Xie, Haijing, Shan, Ying, Zhang, Lin, Cheng, Lin, Chen, Wenyue, Zhu, Rui, Zhang, Kaiwen, Ni, Haosheng, Zhang, Zhenxin, You, Yiwen, You, Bo
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2024; John Wiley and Sons Inc
• Subjects: Acetylation; Acetylation - drug effects; Acetyltransferase; Acetyltransferases - genetics; Acetyltransferases - metabolism; Amino Acid Transport System y+ - antagonists & inhibitors; Amino Acid Transport System y+ - genetics; Amino Acid Transport System y+ - metabolism; Animals; Antibodies; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Antitumor activity; Cancer; Cell cycle; Cell growth; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Enzymes; Female; Ferroptosis; Ferroptosis - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunohistochemistry; Kinases; Lipid peroxidation; Lipids; Male; Mice; Mice, Nude; Molecular modelling; Nasopharyngeal carcinoma; Nasopharyngeal Carcinoma - drug therapy; Nasopharyngeal Carcinoma - genetics; Nasopharyngeal Carcinoma - metabolism; Nasopharyngeal Carcinoma - pathology; Nasopharyngeal Neoplasms - drug therapy; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - metabolism; Nasopharyngeal Neoplasms - pathology; NAT10; Original; Otolaryngology; Plasmids; SLC7A11; Sorafenib - pharmacology; sorafenib resistance; Tumors; Xenograft Model Antitumor Assays; United Kingdom > UK; China; NAT10; nasopharyngeal carcinoma; ferroptosis; SLC7A11; sorafenib resistance
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.16249

Sorafenib, an anticancer drug, has been shown to induce ferroptosis in cancer cells. However, resistance to sorafenib greatly limits its therapeutic efficacy, and the exact mechanism of resistance is not fully understood. This study investigated the role of N‐Acetyltransferase 10 (NAT10) in influencing the anticancer activity of sorafenib in nasopharyngeal carcinoma (NPC) and its molecular mechanism. NAT10 expression was significantly upregulated in NPC. Mechanistically, NAT10 promotes proteins of solute carrier family 7 member 11 (SLC7A11) expression through ac4C acetylation, inhibiting sorafenib‐induced ferroptosis in NPC cells. The combined application of sorafenib and the NAT10 inhibitor remodelin significantly inhibits SLC7A11 expression and promotes ferroptosis in NPC cells. In vivo knockout of NAT10 inhibited the growth of sorafenib‐resistant NPC. Our findings suggest that NAT10 inhibition might be a promising therapeutic approach to enhance the anticancer activity of sorafenib. NAT10 promotes proteins of solute carrier family 7 member 11 (SLC7A11) expression through ac4C acetylation, inhibiting sorafenib‐induced ferroptosis in NPC cells. The combined application of sorafenib and the NAT10 inhibitor remodelin significantly inhibits SLC7A11 expression and promotes ferroptosis in NPC cells. In this study, in vivo knockout of NAT10 inhibited the growth of sorafenib‐resistant NPC. Our findings suggest that NAT10 inhibition might be a promising therapeutic approach to enhance the anticancer activity of sorafenib.