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

Zhengyi Liu; Yang Yu; Shuai Zhou; Xudan Zhang; Zili Zhou

doi:10.1016/j.heliyon.2023.e22599

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

Heliyon. 2023 Nov 20;9(12):e22599. doi: 10.1016/j.heliyon.2023.e22599. eCollection 2023 Dec.

Authors

Zhengyi Liu^{1

2}, Yang Yu¹, Shuai Zhou³, Xudan Zhang⁴, Zili Zhou⁵

Affiliations

¹ Department of Breast Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, Henan Province, 450003, China.
² Microbiome Laboratory, Henan Provincia People's Hospital Zhengzhou University People's Hospital, Zhengzhou, 45270000, China.
³ Translational Research Institute, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, Henan Province, 450003, China.
⁴ Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
⁵ Department of Gastrointestinal Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China.

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.

Keywords: Breast cancer; Deubiquitination; NFκB pathway; Pard3; USP28.