CLK3 regulates tumor angiogenesis by modulating HIF1α ubiquitination

IF 6.4 3区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Cancer gene therapy Pub Date : 2026-07-27 DOI:10.1038/s41417-026-01064-1

Jing Shen, Wen Zhang, Zhiqiang Chu, Lei Zhu, Yan Feng, Xuling Sun

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引用次数: 0

Abstract

Tumor angiogenesis is a critical driver of cancer progression and is regulated by a complex network of signaling pathways. However, limited therapeutic efficacy and the emergence of drug resistance remain significant obstacles, necessitating the exploration of novel angiogenesis inhibitors, alternative pathways, and reliable biomarkers. In this study, we investigate the role of CDC-like kinase 3 (CLK3) in tumor angiogenesis and its underlying molecular mechanisms. Bioinformatic analysis of clinical datasets revealed that CLK3 expression positively correlated with angiogenesis-related pathways in colorectal cancer. In vitro and in vivo experiments confirmed that CLK3 overexpression promoted tumor angiogenesis, whereas CLK3 knockout inhibited this process. Mechanistically, we demonstrated that CLK3 directly interacted with and stabilizes hypoxia-inducible factor 1-alpha (HIF1α) by inhibiting its ubiquitin-proteasome-mediated degradation. Additionally, CLK3 promoted the phosphorylation of HIF1α at tyrosine residues. Furthermore, our functional assays confirmed that CLK3-mediated tumor angiogenesis was dependent on HIF1α. These findings highlight the importance of CLK3 in regulating tumor angiogenesis, and provide compelling evidence for targeting CLK3 as a potential therapeutic strategy for colorectal cancer treatment.

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CLK3通过调控HIF1α泛素化调控肿瘤血管生成。

肿瘤血管生成是癌症进展的关键驱动因素，受复杂的信号通路网络调节。然而，有限的治疗效果和耐药性的出现仍然是重大障碍，需要探索新的血管生成抑制剂，替代途径和可靠的生物标志物。在这项研究中，我们研究了cdc样激酶3 （CLK3）在肿瘤血管生成中的作用及其潜在的分子机制。临床数据集的生物信息学分析显示，CLK3表达与结直肠癌血管生成相关通路呈正相关。体外和体内实验证实，CLK3过表达促进肿瘤血管生成，而敲除CLK3抑制这一过程。在机制上，我们证明CLK3通过抑制其泛素蛋白酶体介导的降解直接与低氧诱导因子1- α (HIF1α)相互作用并稳定其。此外，CLK3促进HIF1α在酪氨酸残基上的磷酸化。此外，我们的功能实验证实clk3介导的肿瘤血管生成依赖于HIF1α。这些发现强调了CLK3在调节肿瘤血管生成中的重要性，并为靶向CLK3作为结直肠癌治疗的潜在治疗策略提供了令人信服的证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer gene therapy 医学-生物工程与应用微生物

CiteScore

10.20

自引率

0.00%

发文量

150

审稿时长

4-8 weeks

期刊介绍： Cancer Gene Therapy is the essential gene and cellular therapy resource for cancer researchers and clinicians, keeping readers up to date with the latest developments in gene and cellular therapies for cancer. The journal publishes original laboratory and clinical research papers, case reports and review articles. Publication topics include RNAi approaches, drug resistance, hematopoietic progenitor cell gene transfer, cancer stem cells, cellular therapies, homologous recombination, ribozyme technology, antisense technology, tumor immunotherapy and tumor suppressors, translational research, cancer therapy, gene delivery systems (viral and non-viral), anti-gene therapy (antisense, siRNA & ribozymes), apoptosis; mechanisms and therapies, vaccine development, immunology and immunotherapy, DNA synthesis and repair. Cancer Gene Therapy publishes the results of laboratory investigations, preclinical studies, and clinical trials in the field of gene transfer/gene therapy and cellular therapies as applied to cancer research. Types of articles published include original research articles; case reports; brief communications; review articles in the main fields of drug resistance/sensitivity, gene therapy, cellular therapy, tumor suppressor and anti-oncogene therapy, cytokine/tumor immunotherapy, etc.; industry perspectives; and letters to the editor.