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USP20 positively regulates tumorigenesis and chemoresistance through ?-catenin stabilization.

ABSTRACT: ?-catenin is a major transcriptional activator of the canonical Wnt/?-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 ?-catenin is frequently observed in cancers, which contributes to survival, metastasis and chemo-resistance of cancer cells. However, the mechanism of ?-catenin overexpression in cancers is not well defined. Here we demonstrate that the deubiquitination enzyme USP20 is a new regulator of the Wnt/?-catenin signaling pathway. Mechanistically, USP20 regulates the deubiquitination of ?-catenin to control its stability, thereby inducing proliferation, invasion and migration of cancer cells. High expression of USP20 correlates with increased ?-catenin protein level in multiple cancer cell lines and patient samples. Moreover, knockdown of USP20 increases ?-catenin polyubiquitination, which enhances ?-catenin turnover and cell sensitivity to chemotherapy. Collectively, our results establish the USP20-?-catenin axis as a critical regulatory mechanism of canonical Wnt/?-catenin signaling pathway with an important role in tumorigenesis and chemo response in human cancers.

SUBMITTER: Wu C

PROVIDER: S-EPMC6180113 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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USP20 positively regulates tumorigenesis and chemoresistance through β-catenin stabilization.

Wu Chenming C Luo Kuntian K Zhao Fei F Yin Ping P Song Ying Y Deng Min M Huang Jinzhou J Chen Yuping Y Li Lei L Lee SeungBaek S Kim JungJin J Zhou Qin Q Tu Xinyi X Nowsheen Somaira S Luo Qifeng Q Gao Xiumei X Lou Zhenkun Z Liu Zhongmin Z Yuan Jian J

Cell death and differentiation 20180604 10

β-catenin is a major transcriptional activator of the canonical Wnt/β-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 β-catenin is frequently observed in cancers, which contributes to survival, metastasis and chemo-resistance of cancer cells. However, the mechanism of β-catenin overexpression in cancers is not well defined. Here we demo ...[more]

PMID: 29867130

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Project description:BackgroundMetastatic breast cancer is responsible for the death of the majority of breast cancer patients. In fact, metastatic BC is the 2nd leading cause of cancer-related deaths in women in the USA and worldwide. Triple negative breast cancer (TNBC), which lacks expression of hormone receptors (ER-α and PR) and ErbB2/HER2, is especially lethal due to its highly metastatic behavior, propensity to recur rapidly, and for its resistance to standard of care therapies, through mechanisms that remain incompletely understood. WAVE3 has been established as a promoter of TNBC development and metastatic progression. In this study, we investigated the molecular mechanisms whereby WAVE3 promotes therapy-resistance and cancer stemness in TNBC, through the regulation of β-catenin stabilization.MethodsThe Cancer Genome Atlas dataset was used to assess the expression of WAVE3 and β-catenin in breast cancer tumors. Kaplan-Meier Plotter analysis was used to correlate expression of WAVE3 and β-catenin with breast cancer patients' survival probability. MTT assay was used to quantify cell survival. CRISPR/Cas9-mediated gene editing, 2D and 3D tumorsphere growth and invasion assays, Immunofluorescence, Western blotting, Semi-quantitative and real-time quantitative PCR analyses were applied to study the WAVE3/β-catenin oncogenic signaling in TNBC. Tumor xenograft assays were used to study the role of WAVE3 in mediating chemotherapy resistance of TNBC tumors.ResultsGenetic inactivation of WAVE3 in combination of chemotherapy resulted in inhibition of 2D growth and 3D tumorsphere formation and invasion of TNBC cells in vitro, as well as tumor growth and metastasis in vivo. In addition, while re-expression of phospho-active WAVE3 in the WAVE3-deficient TNBC cells restored the oncogenic activity of WAVE3, re-expression of phospho-mutant WAVE3 did not. Further studies revealed that dual blocking of WAVE3 expression or phosphorylation in combination with chemotherapy treatment inhibited the activity and expression and stabilization of β-catenin. Most importantly, the combination of WAVE3-deficiency or WAVE3-phospho-deficiency and chemotherapy suppressed the oncogenic behavior of chemoresistant TNBC cells, both in vitro and in vivo.ConclusionWe identified a novel WAVE3/β-catenin oncogenic signaling axis that modulates chemoresistance of TNBC. This study suggests that a targeted therapeutic strategy against WAVE3 could be effective for the treatment of chemoresistant TNBC tumors.

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USP20 positively regulates tumorigenesis and chemoresistance through ?-catenin stabilization.

Publications

USP20 positively regulates tumorigenesis and chemoresistance through β-catenin stabilization.

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