Inhibition of Pard3 promotes breast cancer metastasis via the USP28 mediated deubiquitination of Snail1
Zhengyi Liu,
Yang Yu,
Shuai Zhou,
Xudan Zhang,
Zili Zhou
Affiliations
Zhengyi Liu
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; Microbiome Laboratory, Henan Provincia People's Hospital Zhengzhou University People's Hospital, Zhengzhou, 45270000, China
Yang Yu
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
Shuai Zhou
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
Xudan Zhang
Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
Zili Zhou
Department of Gastrointestinal Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China; Corresponding author. Department of Gastrointestinal Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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.
