O-GlcNAcylation of UBAP2L regulates stress granule formation and sunitinib resistance in clear cell renal cell carcinoma.

IF 12.8 1区 医学 Q1 ONCOLOGY
Jiajun Xing, Baochao Li, Songbo Wang, Zengjun Wang, Chenkui Miao
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Abstract

Background: Sunitinib resistance is one of the main reasons for the poor prognosis of clear renal cell carcinoma (ccRCC). Moreover, Stress granules (SGs) was found to enhance the stress adaptation capability of tumor cells, becoming an important mechanism for drug resistance in various cancers.

Methods: We developed sunitinib-resistant patient-derived xenograft (PDX) and organoid (PDO) models to investigate sunitinib resistance in ccRCC. Proteomic analysis identified UBAP2L as a key mediator of this resistance. To explore its role in stress granule formation and sunitinib resistance, we conducted both in vitro and in vivo studies. We further elucidated the regulatory mechanisms of UBAP2L O-GlcNAcylation using immunoprecipitation, mass spectrometry, modification-based proteomics, RNA sequencing (RNA-seq), and RNA immunoprecipitation sequencing (RIP-seq).

Results: In this study, enrichment of UBAP2L was elucidated to be significantly associated with sunitinib-resistant ccRCC patient-derived xenograft (PDX) model. Functional experiments showed that UBAP2L protected ccRCC from apoptosis and promoted ccRCC prolifecation and angiogenesis upon sunitinib treatment, thus enhancing drug resistance of ccRCC cells. Furthermore, mechanistic investigation demonstrated that O-GlcNAcylation of UBAP2L promoted its protein stability via inhibiting TRIM37-mediated ubiquitination and it regulated stress granule formation, thereby enhancing the mRNA stability of Melk and activating the PI3K signaling pathways.

Conclusions: These results validated the significant roles of O-GlcNAcylation of UBAP2L in ccRCC sunitinib resistance, which provided an innovative theoretical basis for the clinical diagnosis and therapy of ccRCC.

UBAP2L的o - glcn酰化调节透明细胞肾细胞癌的应激颗粒形成和舒尼替尼耐药性。
背景:舒尼替尼耐药是透明肾细胞癌(ccRCC)预后不良的主要原因之一。此外,研究发现应激颗粒(Stress granules, SGs)可增强肿瘤细胞的应激适应能力,成为多种癌症耐药的重要机制。方法:我们建立了舒尼替尼耐药患者来源的异种移植(PDX)和类器官(PDO)模型来研究舒尼替尼在ccRCC中的耐药性。蛋白质组学分析发现UBAP2L是这种抗性的关键媒介。为了探索其在应激颗粒形成和舒尼替尼耐药性中的作用,我们进行了体外和体内研究。我们利用免疫沉淀、质谱、基于修饰的蛋白质组学、RNA测序(RNA-seq)和RNA免疫沉淀测序(RIP-seq)进一步阐明了UBAP2L o - glcn酰化的调控机制。结果:在本研究中,UBAP2L的富集被阐明与舒尼替尼耐药ccRCC患者源异种移植(PDX)模型显著相关。功能实验表明,UBAP2L在舒尼替尼作用下可保护ccRCC细胞免于凋亡,促进ccRCC细胞增殖和血管生成,从而增强ccRCC细胞的耐药性。此外,机制研究表明,UBAP2L的o - glcn酰化通过抑制trim37介导的泛素化而促进其蛋白稳定性,并调节应激颗粒的形成,从而增强Melk mRNA的稳定性,激活PI3K信号通路。结论:这些结果验证了UBAP2L o - glcn酰化在ccRCC舒尼替尼耐药中的重要作用,为ccRCC的临床诊断和治疗提供了创新的理论依据。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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