Abstract
Deubiquitinases (DUBs) have important biological functions, but their roles in breast cancer metastasis are not completely clear. In this study, through screening a series of DUBs related to breast cancer distant metastasis-free survival (DMFS) in the Kaplan-Meier Plotter database, we identified ubiquitin-specific protease 12 (USP12) as a key deubiquitinating enzyme for breast cancer metastasis. We confirmed this via an orthotopic mouse lung metastasis model. We revealed that the DMFS of breast cancer patients with high USP12 was worse than that of others. Knockdown of USP12 decreased the lung metastasis ability of 4T1 cells, while USP12 overexpression increased the lung metastasis ability of these cells in vivo. Furthermore, our results showed that the supernatant from USP12-overexpressing breast cancer cells could promote angiogenesis according to human umbilical vein endothelial cell (HUVEC) migration and tube formation assays. Subsequently, we identified midkine (MDK) as one of its substrates. USP12 could directly interact with MDK, decrease its polyubiquitination and increase its protein stability in cells. Overexpression of MDK rescued the loss of angiogenesis ability mediated by knockdown of USP12 in breast cancer cells in vitro and in vivo. There was a strong positive relationship between USP12 and MDK protein expression in clinical breast cancer samples. Consistent with the pattern for USP12, high MDK expression predicted lower DMFS and overall survival (OS) in breast cancer. Collectively, our study identified that USP12 is responsible for deubiquitinating and stabilizing MDK and leads to metastasis by promoting angiogenesis. Therefore, the USP12–MDK axis could serve as a potential target for the therapeutic treatment of breast cancer metastasis.
Highlights
Breast cancer is the most common malignant tumour in the world [1]
Identification of ubiquitin-specific protease 12 (USP12) as a key molecule in breast cancer metastasis We analysed the relationship between 74 DUBs and the distant metastasis-free survival (DMFS) of breast cancer patients through the KM Plotter database
We found that knocking down USP12 had the most significant inhibitory effect on the lung metastasis of 4T1 cells (Fig. 1B, C)
Summary
It is not the primary tumour but its metastases at distant sites that are the main cause of death [2]. Tumour metastasis is a complex multistep process involving changes in multidimensional analytical network systems such as genomes, transcription groups, proteomics and metabolites. The post-translational modification, ubiquitination and deubiquitination of proteins can cause changes in the molecular network related to tumour metastasis by regulating protein function or degradation. Deubiquitination mediated by many deubiquitinases (DUBs) regulates the level of substrate proteins by cleaving ubiquitin chains and participates in a variety of cellular processes [3, 4]. DUBs have an important role in the process of tumour formation and have bright prospects for tumour treatment, the role and mechanisms of DUBs in the process of breast cancer metastasis are not fully understood
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call