三方基序蛋白65通过增强NKD抑制剂WNT信号通路2泛素化促进前列腺癌增殖和抑制铁下沉。

Chengcai Wang, Huamao Jiang
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引用次数: 0

摘要

作为一种典型的E3连接酶,TRIM65 (tripartite motifi -containing 65)参与了细胞转移、增殖和凋亡等生物过程的调控。然而,TRIM65在前列腺癌(PCa)中的功能及其潜在机制尚不清楚。在这项工作中,我们证实了Tripartite motif-containing protein 65 (TRIM65)在前列腺癌中是一个新的致癌基因,它能加速前列腺癌细胞的增殖,阻碍细胞铁凋亡。在体内,TRIM65的缺失抑制了PCa的肿瘤发生和转移。机械地,我们的发现揭示了TRIM65通过泛素-蛋白酶体信号传导增强WNT信号通路2 (NKD2)降解的NKD抑制剂。TRIM65通过下调NKD2水平促进细胞增殖和抑制铁下垂。此外,TRIM65通过抑制NKD2激活PCa细胞中的无翼整合/β-catenin通路。综上所述,这些数据揭示了TRIM65通过直接靶向NKD2进行泛素化降解来控制PCa增殖和铁凋亡,并调节Wnt/β-catenin信号传导。我们的研究揭示了TRIM65在PCa发展中的多方面调控作用,为探索新的治疗方法奠定了基础。
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Tripartite Motif-Containing Protein 65 Promotes Proliferation and Inhibits Ferroptosis in Prostate Cancer via Enhancing NKD Inhibitor of WNT Signaling Pathway 2 Ubiquitination.

As a typical E3 ligase, tripartite motif-containing 65 (TRIM65), is implicated in the modulation of biological processes, such as metastasis, proliferation, and apoptosis. However, the function of TRIM65 in prostate cancer (PCa) and its potential mechanism have not yet been excavated. In this work, we affirmed Tripartite motif-containing protein 65 (TRIM65) as a new oncogene in PCa, which accelerated PCa cell proliferation and impeded cell ferroptosis. In vivo, depletion of TRIM65 inhibited PCa tumorigenesis and metastasis. Mechanically, our findings uncovered that TRIM65 enhances NKD inhibitor of WNT signaling pathway 2 (NKD2) degradation via the ubiquitin-proteasome signaling. TRIM65 facilitated proliferation and restricted ferroptosis via downregulating NKD2 levels. Moreover, TRIM65 activated the wingless-integrated/β-catenin pathway in PCa cells via inhibiting NKD2. Taken together, these data uncovered that TRIM65 controls PCa proliferation, and ferroptosis and regulates the Wnt/β-catenin signaling via directly targeting NKD2 for ubiquitination degradation. Our study provides insights into the multifaceted regulatory role of TRIM65 in the development of PCa, laying the foundation for exploring new therapeutic approaches.

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