HSPD1通过稳定ATP5A1支持骨肉瘤的进展，从而激活Akt/MTOR信号传导
HSPD1 Supports Osteosarcoma Progression through Stabilizing ATP5A1 and thus Activation of AKT/mTOR Signaling
影响因子:10.00000
分区:生物学1区 Top / 生化与分子生物学2区
发表日期:2024
作者:
Yiming Zhang, Ruilin Pan, Kun Li, Lek Hang Cheang, Jing Zhao, Zhangfeng Zhong, Shaoping Li, Jinghao Wang, Xiaofang Zhang, Yanmei Cheng, Xiaofei Zheng, Rongrong He, Huajun Wang
摘要
恶性转化与应力反应途径的过度激活相关。热休克蛋白（HSP）是应激诱导的蛋白质，在折叠和加工蛋白中起作用，有助于胁迫肿瘤细胞的非癌基因成瘾。但是，尚未研究HSP家族在骨肉瘤中的详细作用。来自GEO和目标数据库的批量和单细胞转录组数据用于识别与骨肉瘤患者预后相关的HSP。骨肉瘤中HSPD1的表达水平显着增加，与负预后相关。通过体外和体内实验，我们系统地鉴定出HSPD1是通过促进上皮 - 间质转变（EMT）和激活AKT/MTOR信号传导来调节骨肉瘤中增殖，转移和凋亡的重要因素。随后，使用免疫沉淀随后进行质谱法确定ATP5A1作为HSPD1的潜在靶标。从机械上讲，HSPD1可能与ATP5A1相互作用，以减少ATP5A1的K48连接的泛素化和降解，这最终激活了AKT/MTOR途径以确保骨肉瘤的进展和EMT过程。这些发现扩大了HSPD1发挥生物学作用的潜在机制，并为其纳入骨肉瘤的潜在治疗靶点提供了有力的证据。
Abstract
Malignant transformation is concomitant with excessive activation of stress response pathways. Heat shock proteins (HSPs) are stress-inducible proteins that play a role in folding and processing proteins, contributing to the non-oncogene addiction of stressed tumor cells. However, the detailed role of the HSP family in osteosarcoma has not been investigated. Bulk and single-cell transcriptomic data from the GEO and TARGET databases were used to identify HSPs associated with prognosis in osteosarcoma patients. The expression level of HSPD1 was markedly increased in osteosarcoma, correlating with a negative prognosis. Through in vitro and in vivo experiments, we systematically identified HSPD1 as an important contributor to the regulation of proliferation, metastasis, and apoptosis in osteosarcoma by promoting the epithelial-mesenchymal transition (EMT) and activating AKT/mTOR signaling. Subsequently, ATP5A1 was determined as a potential target of HSPD1 using immunoprecipitation followed by mass spectrometry. Mechanistically, HSPD1 may interact with ATP5A1 to reduce the K48-linked ubiquitination and degradation of ATP5A1, which ultimately activates the AKT/mTOR pathway to ensure osteosarcoma progression and EMT process. These findings expand the potential mechanisms by which HSPD1 exerts biological effects and provide strong evidence for its inclusion as a potential therapeutic target in osteosarcoma.