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靶向 NAT10 通过 ATF4/ASNS 介导的天冬酰胺合成抑制骨肉瘤进展。

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

机构信息

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.

Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.

出版信息

Cell Rep Med. 2024 Sep 17;5(9):101728. doi: 10.1016/j.xcrm.2024.101728.

DOI:10.1016/j.xcrm.2024.101728
PMID:39293390
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11525028/
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.

摘要

尽管在治疗方面取得了进展，但骨肉瘤患者的预后仍然不尽如人意，因此寻找潜在的治疗靶点至关重要。在这里，我们通过功能筛选发现 N4-乙酰胞苷（ac4C）乙酰转移酶 10（NAT10）是骨肉瘤的候选治疗靶点。NAT10 过表达与预后不良相关，NAT10 敲除抑制骨肉瘤进展。机制上，NAT10 通过 ac4C 修饰增强激活转录因子 4（ATF4）的 mRNA 稳定性。ATF4 诱导天冬酰胺合成酶（ASNS）的转录，催化天冬酰胺（Asn）的合成，促进骨肉瘤的进展。通过虚拟筛选，我们鉴定出帕利哌酮和 AG-401 是潜在的 NAT10 抑制剂，这两种抑制剂都被发现与 NAT10 蛋白结合。抑制 NAT10 可抑制体内骨肉瘤的进展。帕利哌酮和 AG-401 的联合治疗在患者来源的异种移植（PDX）模型中对骨肉瘤产生协同抑制作用。我们的研究结果表明，NAT10 通过 ATF4/ASNS/Asn 轴促进骨肉瘤的进展，抑制 NAT10 的药理学可能是治疗骨肉瘤的一种可行方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/62c9fe0bcebc/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/a6f52327702c/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/ec0827a06c4e/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/7589abfcfeb2/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/064dead8928a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/6e0e6807ebcb/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/9f6ebe43dad0/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/eae0a6373020/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/62c9fe0bcebc/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/a6f52327702c/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/ec0827a06c4e/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/7589abfcfeb2/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/064dead8928a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/6e0e6807ebcb/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/9f6ebe43dad0/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/eae0a6373020/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82aa/11525028/62c9fe0bcebc/gr7.jpg

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