USP20 positively regulates tumorigenesis and chemoresistance through β-catenin stabilization
USP20 positively regulates tumorigenesis and chemoresistance through β-catenin stabilization
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USP20 通过稳定 β-连环蛋白积极调节肿瘤发生和化疗耐药性。
DOI：
10.1038/s41418-018-0138-z
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发表时间：
2018-10-01
影响因子：
12.4
通讯作者：
Yuan, Jian
中科院分区：
文献类型：
--
作者：
Wu, Chenming;Luo, Kuntian;Yuan, Jian
-catenin是典型Wnt/ -catenin信号通路的主要转录激活因子。它在包括组织稳态和胚胎发育在内的一系列生物过程中起着重要作用，并与各种人类疾病有关。在癌症中经常观察到β -连环蛋白的致癌活性升高，这有助于癌细胞的生存、转移和化疗耐药。然而，β -连环蛋白在癌症中的过度表达机制尚不明确。在这里，我们证明了去泛素化酶USP20是Wnt/ β -连环蛋白信号通路的一个新的调节剂。机制上，USP20通过调节β -连环蛋白的去泛素化来控制其稳定性，从而诱导癌细胞的增殖、侵袭和迁移。在多种癌细胞系和患者样本中，USP20的高表达与β -连环蛋白水平升高相关。此外，USP20的敲低增加了β -连环蛋白的多泛素化，从而增强了β -连环蛋白的周转和细胞对化疗的敏感性。总之，我们的研究结果表明usp20 - β -catenin轴是典型Wnt/ β -catenin信号通路的关键调控机制，在人类癌症的肿瘤发生和化疗反应中发挥重要作用。
beta-catenin is a major transcriptional activator of the canonical Wnt/beta-catenin signaling pathway. It is important for a series of biological processes including tissue homeostasis, and embryonic development and is involved in various human diseases. Elevated oncogenic activity of beta-catenin is frequently observed in cancers, which contributes to survival, metastasis and chemo-resistance of cancer cells. However, the mechanism of beta-catenin overexpression in cancers is not well defined. Here we demonstrate that the deubiquitination enzyme USP20 is a new regulator of the Wnt/beta-catenin signaling pathway. Mechanistically, USP20 regulates the deubiquitination of beta-catenin to control its stability, thereby inducing proliferation, invasion and migration of cancer cells. High expression of USP20 correlates with increased beta-catenin protein level in multiple cancer cell lines and patient samples. Moreover, knockdown of USP20 increases beta-catenin polyubiquitination, which enhances beta-catenin turnover and cell sensitivity to chemotherapy. Collectively, our results establish the USP20-beta-catenin axis as a critical regulatory mechanism of canonical Wnt/beta-catenin signaling pathway with an important role in tumorigenesis and chemo response in human cancers.