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

IF 11.7 1区 医学 Q1 CELL BIOLOGY Cell Reports Medicine Pub Date : 2024-09-17 DOI:10.1016/j.xcrm.2024.101728
Yutong Zou, Siyao Guo, Lili Wen, Dongming Lv, Jian Tu, Yan Liao, Weidong Chen, Ziyun Chen, Hongbo Li, Junkai Chen, Jingnan Shen, Xianbiao Xie
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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.

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靶向 NAT10 可通过 ATF4/ASNS 介导的天冬酰胺生物合成抑制骨肉瘤进展
尽管在治疗方面取得了进展,但骨肉瘤患者的预后仍不令人满意,因此寻找潜在靶点势在必行。在这里,我们通过功能筛选确定了N4-乙酰胞苷(ac4C)乙酰转移酶10(NAT10)作为骨肉瘤的候选治疗靶点。NAT10过表达与预后不良相关,而NAT10敲除可抑制骨肉瘤的进展。从机理上讲,NAT10通过ac4C修饰增强活化转录因子4(ATF4)的mRNA稳定性。ATF4 可诱导天冬酰胺合成酶(ASNS)的转录,ASNS 可催化天冬酰胺(Asn)的生物合成,从而促进骨肉瘤的进展。通过虚拟筛选,我们发现帕利哌酮和AG-401是潜在的NAT10抑制剂,这两种抑制剂都能与NAT10蛋白结合。抑制 NAT10 可抑制骨肉瘤在体内的发展。帕利哌酮和AG-401联合治疗可在患者异种移植(PDX)模型中产生协同抑制骨肉瘤的作用。我们的研究结果表明,NAT10通过ATF4/ASNS/Asn轴促进骨肉瘤的进展,药理抑制NAT10可能是治疗骨肉瘤的一种可行方法。
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来源期刊
Cell Reports Medicine
Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
15.00
自引率
1.40%
发文量
231
审稿时长
40 days
期刊介绍: Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.
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