ArticleCell death & disease2021
USP12 promotes breast cancer angiogenesis by maintaining midkine stability.
Article in Cell death & disease, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- Stress-Induced Activation of Prolactin-NR4A1-Midkine Axis Exacerbates Skin Inflammation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Pathological role of deubiquitinating enzymes in lung cancer: recent insights and advances.American journal of cancer research · 2026Review
- Ubiquitin-specific protease 5 promotes breast cancer progression by stabilizing Forkhead box M1 through deubiquitination.CytoJournal · 2026Article
- UCHL1 stabilizes Twist1 via K11/K63-linked deubiquitination to drive tumor metastasis in non-small cell lung cancer.Cell death discovery · 2025Article
- Significance of Midkine Signaling in Women's Cancers: Novel Biomarker and Therapeutic Target.International journal of molecular sciences · 2025Review
- Deubiquitinating Enzymes in Osteoarthritis: From Mechanisms to Therapeutic.Orthopedic reviews · 2025Article
- The estrogen response in fibroblasts promotes ovarian metastases of gastric cancer.Nature communications · 2024Article
- Midkine: A Cancer Biomarker Candidate and Innovative Therapeutic Approaches.European journal of breast health · 2024Article
- Deubiquitinating enzymes: potential regulators of the tumor microenvironment and implications for immune evasion.Cell communication and signaling : CCS · 2024Review
- Single-Cell RNA Sequencing Reveals Transcriptional Signatures and Cell-Cell Communication in Diabetic Retinopathy.Endocrine, metabolic & immune disorders drug targets · 2024Article
- Deubiquitylating Enzymes in Cancer and Immunity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Review
- Spotlights on ubiquitin-specific protease 12 (USP12) in diseases: from multifaceted roles to pathophysiological mechanisms.Journal of translational medicine · 2023Review
- Article
- Midkine noncanonically suppresses AMPK activation through disrupting the LKB1-STRAD-Mo25 complex.Cell death & disease · 2022Article
- Targeting MDK Abrogates IFN-γ-Elicited Metastasis inCancers of Various Origins.Frontiers in oncology · 2022Article
- The role of ubiquitination and deubiquitination in tumor invasion and metastasis.International journal of biological sciences · 2022Review
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Authors and funding
5 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
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