The deubiquitinase USP15 drives malignant progression of gastric cancer through glucose metabolism remodeling.

IF 11.4 1区 医学 Q1 ONCOLOGY
Longtao Huangfu, Huanbo Zhu, Gangjian Wang, Junbing Chen, Yongqi Wang, Biao Fan, Xiaoyang Wang, Qian Yao, Ting Guo, Jing Han, Ying Hu, Hong Du, Xiaomei Li, Jiafu Ji, Xiaofang Xing
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Abstract

Background: Ubiquitin-specific protease 15 (USP15) exhibits amplifications in various tumors, including gastric cancer (GC), yet its biological function and mechanisms in GC progression remain elusive.

Methods: Here, we established stable USP15 knockdown or overexpression GC cell lines and explored the potential mechanism of USP15 in GC. Besides, we also identified interacting targets of USP15.

Results: USP15 knockdown significantly impeded cell proliferation, invasion, epithelial-mesenchymal transition, and distal colonization in xenograft models, while enhancing oxaliplatin's antitumor effect. USP15 was involved in ubiquitination modification of glycolytic regulators. Silencing of USP15 suppressed glycolytic activity and impaired mitochondrial functions. Interference with USP15 expression reversed tumor progression and distal colonization in vivo. HKDC1 and IGF2BP3 were found as core interacting targets of USP15, and HKDC1 was identified as a substrate for ubiquitination modification by USP15, whereby USP15 regulated glucose metabolism activity by inhibiting the ubiquitination degradation of HKDC1.

Conclusions: Our study unveiled aberrantly high expression of USP15 in GC tissues, correlating with malignant progression and nonresponse to neoadjuvant therapy. USP15 inhibitors, if developed, could be effective in promoting chemotherapy through glucose metabolism remodeling.

去泛素化酶USP15通过葡萄糖代谢重塑驱动胃癌恶性进展
背景:方法:我们建立了稳定的 USP15 敲除或过表达 GC 细胞系,并探索了 USP15 在 GC 中的潜在机制。此外,我们还发现了USP15的相互作用靶点:结果:在异种移植模型中,敲除 USP15 能明显抑制细胞增殖、侵袭、上皮-间质转化和远端定植,同时增强奥沙利铂的抗肿瘤效果。USP15 参与了糖酵解调节因子的泛素化修饰。沉默 USP15 会抑制糖酵解活性并损害线粒体功能。干扰 USP15 的表达可逆转体内肿瘤的进展和远端定植。研究发现,HKDC1和IGF2BP3是USP15的核心相互作用靶标,HKDC1是USP15泛素化修饰的底物,USP15通过抑制HKDC1的泛素化降解来调节糖代谢活性:我们的研究揭示了 USP15 在 GC 组织中的异常高表达,这与恶性进展和对新辅助治疗无反应有关。如果开发出 USP15 抑制剂,可通过重塑葡萄糖代谢有效促进化疗。
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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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