HSPD1通过稳定ATP5A1支持骨肉瘤的进展，从而激活AKT/mTOR信号通路

HSPD1 Supports Osteosarcoma Progression through Stabilizing ATP5A1 and thus Activation of AKT/mTOR Signaling

International Journal of Biological Sciences

影响因子:10

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

DOI: 10.7150/ijbs.100015

摘要

恶性转化伴随着应激反应通路的过度激活。热休克蛋白（HSPs）是应激诱导的蛋白，参与蛋白质的折叠和处理，有助于应激肿瘤细胞的非致癌性依赖。然而，HSP家族在骨肉瘤中的具体作用尚未被研究。利用GEO和TARGET数据库中的批量及单细胞转录组数据，鉴定出与骨肉瘤患者预后相关的HSP。HSPD1的表达水平在骨肉瘤中显著升高，且与预后不良相关。通过体外和体内实验，我们系统性地确认HSPD1通过促进上皮-间质转化（EMT）和激活AKT/mTOR信号途径，调节骨肉瘤的增殖、转移和凋亡。随后，利用免疫沉淀结合质谱分析，确定ATP5A1为HSPD1的潜在靶标。机制上，HSPD1可能与ATP5A1相互作用，减少ATP5A1的K48连接的泛素化及其降解，最终激活AKT/mTOR通路，确保骨肉瘤的进展和EMT过程。这些发现拓展了HSPD1发挥生物学作用的潜在机制，为其作为骨肉瘤潜在治疗靶点提供了有力证据。

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.