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向NAT10可以通过ATF4/ASNS介导的阿斯帕拉金生物合成来抑制骨肉瘤的进展

Yutong Zou¹, Siyao Guo², Lili Wen³

¹Department 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.

Cell reports. Medicine

|September 18, 2024

概括

通过稳定激活转录因子4 (ATF4) 的mRNA,N4-乙基提丁乙转移酶10 (NAT10) 驱动骨肉瘤的进展. 用像帕利佩里这样的药物抑制NAT10为骨髓瘤提供了一个有前途的治疗策略.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
生物化学生物化学

背景情况:

尽管治疗进展,骨肉瘤的预后仍然很差,需要新的治疗点.
N4-乙基丁 (ac4C) 乙转移酶10 (NAT10) 已成为癌症进展中的潜在参与者.

研究的目的:

研究NAT10作为骨髓瘤的治疗点.
阐明NAT10影响骨髓瘤进展的分子机制.

主要方法:

功能查以确定NAT10作为目标.
NAT10淘汰和过度表达的研究.
对mRNA稳定性和基因转录 (ATF4,ASNS) 的分析.
对NAT10抑制剂 (paliperidone,AG-401) 的虚拟查.
使用骨髓瘤细胞系和患者衍生异种移植 (PDX) 模型的体内研究.

主要成果:

过度表达NAT10与骨髓瘤预后不佳相关.
NAT10淘汰赛可以抑制骨髓瘤的进展.
NAT10通过ac4C修饰增强ATF4mRNA的稳定性,促进ASNS转录和阿斯巴拉金生物合成.
帕利佩里和AG-401与NAT10结合并抑制其活性.
在体内,NAT10抑制抑制骨髓瘤的进展,在联合药物治疗中观察到协同效应.

结论:

NAT10通过ATF4/ASNS/阿斯巴拉金轴促进骨肉瘤的进展.
药理上抑制NAT10是一种可行的骨髓瘤治疗策略.

关键词:

在 ASNS 系统中,ASNS 是在ATF4中使用ATF4.这是一种N4-乙基胺.在 NAT10 中,NAT10 包含了NAT10.阿斯巴拉基因 (asparagine) 是一种骨质肉瘤是骨质肉瘤的一种疾病.

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