CUL4A exhibits tumor-suppressing role via regulation of HUWE1-mediated SMAD3 intracellular shuttling

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-03-20 DOI:10.1016/j.canlet.2025.217663

Veronika Danek , Jolana Tureckova , Kerstin Huebner , Katharina Erlenbach-Wuensch , Petra Baranova , Jan Dobes , Jana Balounova , Michaela Simova , Vendula Novosadova , Carlos Eduardo Madureira Trufen , Michaela Prochazkova , Pavel Talacko , Karel Harant , Cyril Barinka , Inken M. Beck , Regine Schneider-Stock , Radislav Sedlacek , Jan Prochazka

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引用次数: 0

Abstract

Changes in cellular physiology and proteomic homeostasis accompanied the initiation and progression of colorectal cancer. Thus, ubiquitination represents a central regulatory mechanism in proteome dynamics. However, the complexity of the ubiquitinating network involved in carcinogenesis remains unclear. This study revealed the tumor-suppressive role of the ubiquitin ligase Cullin4A (CUL4A) in the intestine. We showed that simultaneous loss of CUL4A and hyperactivation of the Wnt pathway promotes tumor development in the distal colon. This tumor development is caused by an accumulation of the inactive SMAD3, a TGF-β pathway mediator. Depletion of CUL4A resulted in stabilization of HUWE1, which attenuated SMAD3 function. We showed a correlation between the intracellular localization of CUL4A and colorectal cancer progression, where nuclear CUL4A localization correlates with advanced colorectal cancer progression. In summary, we identified CUL4A as an important regulator of SMAD3 signal transduction competence in a HUWE1-dependent manner and demonstrated a critical role for the crosstalk between ubiquitination and the Wnt/TGF-β signaling pathways in gastrointestinal homeostasis.

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CUL4A通过调节huwe1介导的SMAD3细胞内穿梭表现出肿瘤抑制作用。

细胞生理和蛋白质组动态平衡的变化伴随着结直肠癌的发生和发展。因此，泛素化代表了蛋白质组动力学的中心调控机制。然而，泛素化网络参与癌变的复杂性仍不清楚。本研究揭示了肠道中泛素连接酶Cullin4A （CUL4A）的肿瘤抑制作用。我们发现CUL4A的同时缺失和Wnt通路的过度激活促进了远端结肠肿瘤的发展。这种肿瘤的发展是由无活性的SMAD3（一种TGF-β通路介质）的积累引起的。CUL4A的缺失导致HUWE1的稳定，从而减弱SMAD3的功能。我们发现CUL4A的细胞内定位与结直肠癌进展之间存在相关性，其中细胞核CUL4A定位与晚期结直肠癌进展相关。综上所述，我们发现CUL4A是SMAD3信号转导能力的重要调节因子，以huwe1依赖的方式，并且在胃肠道稳态中泛素化和Wnt/TGF-β信号通路之间的串串中发挥关键作用。

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 letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.