USP12 promotes breast cancer angiogenesis by maintaining midkine stability

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 ident...

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Autores principales:	Bin Sheng, Zichao Wei, Xiaowei Wu, Yi Li, Zhihua Liu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Cytology QH573-671
Acceso en línea:	https://doaj.org/article/636c63763e4847b0a3eab9c7b3377f3c
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spelling	oai:doaj.org-article:636c63763e4847b0a3eab9c7b3377f3c2021-11-14T12:06:50ZUSP12 promotes breast cancer angiogenesis by maintaining midkine stability10.1038/s41419-021-04102-y2041-4889https://doaj.org/article/636c63763e4847b0a3eab9c7b3377f3c2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04102-yhttps://doaj.org/toc/2041-4889Abstract 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.Bin ShengZichao WeiXiaowei WuYi LiZhihua LiuNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 11, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytology QH573-671
spellingShingle	Cytology QH573-671 Bin Sheng Zichao Wei Xiaowei Wu Yi Li Zhihua Liu USP12 promotes breast cancer angiogenesis by maintaining midkine stability
description	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.
format	article
author	Bin Sheng Zichao Wei Xiaowei Wu Yi Li Zhihua Liu
author_facet	Bin Sheng Zichao Wei Xiaowei Wu Yi Li Zhihua Liu
author_sort	Bin Sheng
title	USP12 promotes breast cancer angiogenesis by maintaining midkine stability
title_short	USP12 promotes breast cancer angiogenesis by maintaining midkine stability
title_full	USP12 promotes breast cancer angiogenesis by maintaining midkine stability
title_fullStr	USP12 promotes breast cancer angiogenesis by maintaining midkine stability
title_full_unstemmed	USP12 promotes breast cancer angiogenesis by maintaining midkine stability
title_sort	usp12 promotes breast cancer angiogenesis by maintaining midkine stability
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/636c63763e4847b0a3eab9c7b3377f3c
work_keys_str_mv	AT binsheng usp12promotesbreastcancerangiogenesisbymaintainingmidkinestability AT zichaowei usp12promotesbreastcancerangiogenesisbymaintainingmidkinestability AT xiaoweiwu usp12promotesbreastcancerangiogenesisbymaintainingmidkinestability AT yili usp12promotesbreastcancerangiogenesisbymaintainingmidkinestability AT zhihualiu usp12promotesbreastcancerangiogenesisbymaintainingmidkinestability
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USP12 promotes breast cancer angiogenesis by maintaining midkine stability

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