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Protein Phosphatase 1 Subunit PPP1R14B Stabilizes STMN1 to Promote Progression and Paclitaxel Resistance in Triple-Negative Breast Cancer

三阴性乳腺癌 紫杉醇 癌症研究 蛋白质亚单位 生物 蛋白磷酸酶2 癌症 乳腺癌 三重阴性 内科学 肿瘤科 医学 磷酸酶 生物化学 基因
作者
Li Liao,Yin-Ling Zhang,Ling Deng,Chao Chen,Xiao-Yan Ma,Lisa Andriani,Shao‐Ying Yang,Shu‐Yuan Hu,Fang-Lin Zhang,Zhimin Shao,Da‐Qiang Li
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:83 (3): 471-484 被引量:37
标识
DOI:10.1158/0008-5472.can-22-2709
摘要

Triple-negative breast cancer (TNBC) represents the most lethal subtype of breast cancer due to its aggressive clinical features and the lack of effective therapeutic targets. To identify novel approaches for targeting TNBC, we examined the role of protein phosphatases in TNBC progression and chemoresistance. Protein phosphatase 1 regulatory subunit 14B (PPP1R14B), a poorly defined member of the protein phosphatase 1 regulatory subunits, was aberrantly upregulated in TNBC tissues and predicted poor prognosis. PPP1R14B was degraded mainly through the ubiquitin-proteasome pathway. RPS27A recruited deubiquitinase USP9X to deubiquitinate and stabilize PPP1R14B, resulting in overexpression of PPP1R14B in TNBC tissues. Gain- and loss-of-function assays demonstrated that PPP1R14B promoted TNBC cell proliferation, colony formation, migration, invasion, and resistance to paclitaxel in vitro. PPP1R14B also induced xenograft tumor growth, lung metastasis, and paclitaxel resistance in vivo. Mechanistic investigations revealed that PPP1R14B maintained phosphorylation and stability of oncoprotein stathmin 1 (STMN1), a microtubule-destabilizing phosphoprotein critically involved in cancer progression and paclitaxel resistance, which was dependent on PP1 catalytic subunits α and γ. Importantly, the tumor-suppressive effects of PPP1R14B deficiency could be partially rescued by ectopic expression of wild-type but not phosphorylation-deficient STMN1. Moreover, PPP1R14B decreased STMN1-mediated α-tubulin acetylation, microtubule stability, and promoted cell-cycle progression, leading to resistance of TNBC cells to paclitaxel. Collectively, these findings uncover a functional and mechanistic role of PPP1R14B in TNBC progression and paclitaxel resistance, indicating PPP1R14B is a potential therapeutic target for TNBC.PPP1R14B upregulation induced by RPS27A/USP9X in TNBC increases STMN1 activity, leading to cancer progression and paclitaxel resistance.

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