2. Academic Validation
  3. Targeting NAT10 inhibits osteosarcoma progression via ATF4/ASNS-mediated asparagine biosynthesis

Targeting NAT10 inhibits osteosarcoma progression via ATF4/ASNS-mediated asparagine biosynthesis

  • Cell Rep Med. 2024 Sep 17;5(9):101728. doi: 10.1016/j.xcrm.2024.101728.
Yutong Zou 1,  Siyao Guo 2,  Lili Wen 3,  Dongming Lv 4,  Jian Tu 1,  Yan Liao 1,  Weidong Chen 1,  Ziyun Chen 1,  Hongbo Li 1,  Junkai Chen 1,  Jingnan Shen 5,  Xianbiao Xie 6
Affiliations

Affiliations

  • 1 Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong, China.
  • 2 Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 3 Department of Anesthesiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
  • 4 Department of Burns, Wound Repair and Reconstruction, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 5 Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong, China. Electronic address: shenjn@mail.sysu.edu.cn.
  • 6 Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong, China. Electronic address: xiexbiao@mail.sysu.edu.cn.
PMID: 39293390 DOI: 10.1016/j.xcrm.2024.101728
Abstract

Despite advances in treatment, the prognosis of patients with osteosarcoma remains unsatisfactory, and searching for potential targets is imperative. Here, we identify N4-acetylcytidine (ac4C) acetyltransferase 10 (NAT10) as a candidate therapeutic target in osteosarcoma through functional screening. NAT10 overexpression is correlated with a poor prognosis, and NAT10 knockout inhibits osteosarcoma progression. Mechanistically, NAT10 enhances mRNA stability of activating transcription factor 4 (ATF4) through ac4C modification. ATF4 induces the transcription of asparagine synthetase (ASNS), which catalyzes asparagine (Asn) biosynthesis, facilitating osteosarcoma progression. Utilizing virtual screening, we identify paliperidone and AG-401 as potential NAT10 inhibitors, and both inhibitors are found to bind to NAT10 proteins. Inhibiting NAT10 suppresses osteosarcoma progression in vivo. Combined treatment using paliperidone and AG-401 produces synergistic inhibition for osteosarcoma in patient-derived xenograft (PDX) models. Our findings demonstrate that NAT10 facilitates osteosarcoma progression through the ATF4/ASNS/Asn axis, and pharmacological inhibition of NAT10 may be a feasible therapeutic approach for osteosarcoma.

Keywords

ASNS; ATF4; N4-acetylcytidine; NAT10; asparagine; osteosarcoma.

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