USP1 inhibition destabilizes KPNA2 and suppresses breast cancer metastasis.

Abstract

Metastatic progression is the main cause of mortality in breast cancer, necessitating the determination of the molecular events driving this process for the development of new therapeutic approaches. Here, we demonstrate that hyperactivation of the deubiquitinase USP1 contributes to breast cancer metastasis. Upregulated USP1 expression in primary breast cancer specimens correlates with metastatic progression and poor prognosis in breast cancer patients. USP1 enhances the expression of a number of pro-metastatic genes in breast cancer cells, promotes cell migration and invasion in vitro, and facilitates lung metastasis of breast cancer cells. Moreover, USP1-mediated deubiquitination and stabilization of KPNA2 are revealed as the downstream events crucial for USP1-pro-metastatic function. Most importantly, pharmacological intervention of USP1 function by pimozide or ML323 significantly represses breast cancer metastasis in mice, suggesting a rationale for using USP1 inhibitors for treatment of patients with breast cancer. Taken together, our results establish USP1 as a promoter of breast cancer metastasis and provide evidence for the potential practice of USP1 targeting in the treatment of breast cancer.

• Authors: Aihui Ma, Ming Tang, Li Zhang, Boshi Wang, Zhaojuan Yang, Yun Liu, Guiqin Xu, Lin Wu, Tiantian Jing, Xiaoli Xu, Shengli Yang, Yongzhong Liu
• Journal: Oncogene (Oncogene) Vol. 38 Issue 13 Pg. 2405-2419 (03 2019) ISSN: 1476-5594 [Electronic] England
• PMID: 30531833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• KPNA2 protein, human
• alpha Karyopherins
• USP1 protein, human
• Ubiquitin-Specific Proteases

Topics

• Animals
• Breast Neoplasms (metabolism, pathology)
• Cell Line
• Cell Line, Tumor
• Cell Movement (physiology)
• Disease Progression
• Female
• HEK293 Cells
• Humans
• Lung Neoplasms (metabolism, pathology)
• MCF-7 Cells
• Mice
• Mice, Inbred BALB C
• Neoplasm Invasiveness (pathology)
• Neoplasm Metastasis (pathology)
• Prognosis
• Promoter Regions, Genetic (physiology)
• Ubiquitin-Specific Proteases (antagonists & inhibitors)
• alpha Karyopherins (metabolism)