去泛素化酶 USP9X 通过稳定 Snail1 调节三阴性乳腺癌的转移和化疗耐药,Journal of Cellular Physiology

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去泛素化酶 USP9X 通过稳定 Snail1 调节三阴性乳腺癌的转移和化疗耐药
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2022-05-03 , DOI: 10.1002/jcp.30763
Tangming Guan ₁ , Xiao Yang ₁ , Hui Liang ₁ , Jiayi Chen ₁ , Yan Chen ₂ , Yingjie Zhu ₁ , Tongzheng Liu ₁

Affiliation

乳腺癌是全世界女性最常见的恶性肿瘤之一。三阴性乳腺癌（TNBC）是一种高度侵袭性和转移性的亚型，具有易复发、预后差、缺乏靶向治疗的特点。Snail1 是调节上皮-间质转化 (EMT) 过程的关键因子，有助于人类癌症的转移和化学抗性。然而，Snail1 在癌症中稳定的分子机制尚不完全清楚。在这里，我们证明去泛素化酶 USP9X 去泛素化并稳定 Snail1，从而促进转移和化学抗性。USP9X 抑制剂 WP1130 对 USP9X 的消耗和药理抑制作用，下调内源性 Snail1 蛋白，抑制细胞迁移、侵袭、转移，并在体外和体内增加细胞对顺铂和紫杉醇的敏感性，而在 USP9X 耗尽的细胞中重组 Snail1 至少部分逆转了这些表型。总体而言，我们的研究确立了 USP9X-Snail1 轴作为乳腺癌转移和化疗耐药的重要调节机制，并为 TNBC 治疗中的潜在治疗干预提供了理论基础。

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Deubiquitinating enzyme USP9X regulates metastasis and chemoresistance in triple-negative breast cancer by stabilizing Snail1

Breast cancer is one of the most common malignancies in women worldwide. Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic subtype that has the characteristics of easy recurrence, poor prognosis as well as lack of targeted therapeutics. Snail1, a key factor regulating epithelial–mesenchymal transition (EMT) process, contributing to metastasis and chemoresistance in human cancers. However, the molecular mechanism of Snail1 stabilization in cancers is not fully understood. Here, we demonstrate that the deubiquitinating enzyme USP9X deubiquitinates and stabilizes Snail1, thereby promoting metastasis and chemoresistance. The depletion and pharmacological inhibition of USP9X by WP1130, an inhibitor of USP9X, downregulate endogenous Snail1 protein, inhibit cell migration, invasion, metastasis, and increase cellular sensitivity to cisplatin and paclitaxel both in vitro and in vivo, whereas the reconstitution of Snail1 in cells with USP9X depletion at least partially reverses these phenotypes. Overall, our study establishes the USP9X-Snail1 axis as an important regulatory mechanism of breast cancer metastasis and chemoresistance and provides a rationale for potential therapeutic interventions in the treatment of TNBC.

更新日期：2022-05-03

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