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Inhibition of Pard3 promotes breast cancer metastasis via the USP28 mediated deubiquitination of Snail1.

ABSTRACT: Pard3 is a core component of the Par complex and is a critical regulator of cell polarity. However, the biological role of Pard3 in breast cancer (BC) remains unclear. In this study we found that Pard3 levels were down-regulated in BC cells and tissues. Pard3 down-regulation was associated with the TNM stage of BC. Further, Pard3 knockdown enhanced colony formation and metastasis in vitro and in vivo. Interestingly, Pard3 knockdown also enhanced Snail1 deubiquitination and promoted BC invasion and migration via Snail1. Moreover, Pard3 silencing led to activation of the NFκB pathway, promoting the expression of USP28. Subsequently, USP28 interacted with and deubiquitinated Snail1; these effects were dependent on GSK-3β-mediated phosphorylation. Together, the findings indicated that Pard3 knockdown facilitated the migration and invasion of BC cells by enhancing USP28-mediated Snail1 deubiquitination. Collectively, targeting the Pard3/NFκB/USP28/Snail1 signaling pathway might be a promising treatment option for breast cancer.

SUBMITTER: Liu Z

PROVIDER: S-EPMC10709364 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Inhibition of Pard3 promotes breast cancer metastasis via the USP28 mediated deubiquitination of Snail1.

Liu Zhengyi Z Yu Yang Y Zhou Shuai S Zhang Xudan X Zhou Zili Z

Heliyon 20231120 12

Pard3 is a core component of the Par complex and is a critical regulator of cell polarity. However, the biological role of Pard3 in breast cancer (BC) remains unclear. In this study we found that Pard3 levels were down-regulated in BC cells and tissues. Pard3 down-regulation was associated with the TNM stage of BC. Further, Pard3 knockdown enhanced colony formation and metastasis in vitro and in vivo. Interestingly, Pard3 knockdown also enhanced Snail1 deubiquitination and promoted BC invasion a ...[more]

PMID: 38076191

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Project description:Breast cancer has become the malignant disease with the highest morbidity and mortality among female cancer patients. The prognosis of metastatic breast cancer is very poor, and the therapeutic effects still need to be improved. The molecular mechanism of breast cancer has not been fully clarified. Bioinformatics analysis was used to find the differentially expressed gene that affects the occurrence and development of breast cancer. Furthermore, scratch assays, Transwell assays, immunofluorescence, and Western blotting were used to determine the biological behavior of breast cancer cells affected by DEP domain-containing protein 1B (DEPDC1B). The molecular mechanism was investigated by mass spectrometry analysis, coimmunoprecipitation, and ubiquitin assays. Here, we found that DEPDC1B was highly expressed in breast cancer cells and tissues and was associated with lower overall survival (OS) in patients. We found that DEPDC1B interference significantly inhibited tumor invasion and migration in vitro and tumor metastasis in vivo. Mechanistically, DEPDC1B was first shown to activate the wnt/β-catenin signaling pathway as an oncogene in breast cancer cells. In addition, we also confirmed the interaction between DEPDC1B, ubiquitin-specific protease 5 (USP5), and β-catenin. Then, we found that DEPDC1B mediates the deubiquitination of β-catenin via USP5, which promotes cell invasion and migration. Our findings provide new insights into the carcinogenic mechanism of DEPDC1B, suggesting that DEPDC1B can be considered a potential therapeutic target for breast cancer.NEW & NOTEWORTHY By using bioinformatics analysis and the experimental techniques of cell biology and molecular biology, we found that DEP domain-containing protein 1B (DEPDC1B) can promote the invasion and migration of breast cancer cells and that DEPDC1B mediates the deubiquitination of β-catenin by ubiquitin-specific protease 5 (USP5), thus activating the wnt/β-catenin pathway. Our findings provide new insights into the carcinogenic mechanism of DEPDC1B, suggesting that DEPDC1B can be used as a potential therapeutic target for breast cancer.

Dataset Information

Inhibition of Pard3 promotes breast cancer metastasis via the USP28 mediated deubiquitination of Snail1.

Publications

Inhibition of Pard3 promotes breast cancer metastasis via the USP28 mediated deubiquitination of Snail1.

Similar Datasets

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