Deubiquitinase USP10 regulates Notch signaling in the endothelium

Lim, Radiance; Sugino, Toshiya; Nolte, Hendrik; Andrade, Jorge; Zimmermann, Bárbara H.; Shi, Chenyue; Doddaballapur, Anuradha; Ong, Yu Ting; Wilhelm, Kerstin; Fasse, J. W. D.; Ernst, Andreas; Kaulich, Manuel; Husnjak, Koraljka; Boettger, Thomas; Guenther, Stefan; Braun, Thomas; Krüger, Marcus; Benedito, Rui; Đikić, Ivan; Potente, Michael

doi:10.1126/science.aat0778

Cited by 70 publications

(35 citation statements)

References 43 publications

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“…The Notch pathway is a well-ordered, evolutionary conserved pathway and crucial to the regulation of morphological development in multicellular organisms that governs connections between interacting cells (12,13). Dysregulation in Notch signaling transduction is related to various genetic diseases, including cancers (14,15).…”

Section: Introductionmentioning

confidence: 99%

Cooperation Between Cancer and Fibroblasts in Vascular Mimicry and N2-Type Neutrophil Recruitment via Notch2–Jagged1 Interaction in Lung Cancer

Tsai

Liu

et al. 2021

Front. Oncol.

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BackgroundAngiogenesis is required for tumor development and metastasis, which is a major part in a pro-tumor microenvironment. Vascular mimicry (VM) is a process in which cancer cells, rather than endothelia, create an alternative perfusion system to support the tumor progression.ObjectivesTo validate the role of VM and to develop a strategy to inhibit angiogenesis in lung cancer.MethodsIn this study, we utilized lung cancer samples to verify the existence of VM and conducted several experimental methods to elucidate the molecular pathways.ResultsH1299 and CL1-0 lung cancer cells were unable to form capillary-like structures. VM formation was induced by cancer-associated fibroblast (CAFs) in both in vitro and in vivo experiments. Notch2–Jagged1 cell–cell contact between cancer cells and CAFs contributes to the formation of VM networks, supported by Notch intracellular domain (NICD) 2 nuclear translocation and N2ICD target gene upregulated in lung cancer cells mixed with CAFs. The polarization of tumor-promoting N2-type neutrophil was increased by VM networks consisting of CAF and cancer cells. The intravasation of cancer cells and N2-type neutrophils were increased because of the loose junctions of VM. Disruption of cancer cell–CAF connections by a γ‐secretase inhibitor enforced the anticancer effect of anti‐vascular endothelial growth factor antibodies in a mouse model.ConclusionThis study provides the first evidence that CAFs induce lung cancer to create vascular-like networks. These findings suggest a therapeutic opportunity for improving antiangiogenesis therapy in lung cancer.

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Section: Introductionmentioning

confidence: 99%

Cooperation Between Cancer and Fibroblasts in Vascular Mimicry and N2-Type Neutrophil Recruitment via Notch2–Jagged1 Interaction in Lung Cancer

Tsai

Liu

et al. 2021

Front. Oncol.

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“…In addition, myocardial fibrosis in perivascular and interstitial spaces were significantly increased in USP10-CKO mice ( Zhang et al, 2020 ). Research on the endothelium revealed that USP10, as a regulatory protein, delayed the rate of NICD1 degradation by deubiquitinating the Notch1 receptor ( Lim et al, 2019 ). Consistent with the above findings, we further examined the changes in FSTL1 and USP10 in T2DM with and without MI and investigated the relationship between FSTL1 and USP10/Notch1 signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Ubiquitin-specific protease 10 (USP10) is a deubiquitinase that catalyzes the hydrolysis reaction and removes conjugated ubiquitin from its target proteins. In response to cell stress, USP10 was translocated from the cytoplasm to the nucleus to regulate cell cycle and apoptosis ( Lim et al, 2019 ; Zhang et al, 2020 ). Previous studies demonstrated that USP10 protected cells against pathological injury in numerous organs ( Yuan et al, 2010 ; Deng et al, 2016 ; Wang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of USP10 exacerbated cardiac hypertrophy by regulating sirtuin 6 (Sirt6) signaling ( Zhang et al, 2020 ). In the endothelium, USP10 functioned as a NICD1 deubiquitinase that fine-tuned endothelial Notch signaling responses during angiogenic sprouting ( Lim et al, 2019 ). Our earlier report revealed that upregulation of Notch1 ligand Jagged-1 and its intracellular domain decreased transverse aortic constriction-induced myocardial fibrosis, which could be reversed by Notch inhibition ( Chen X. et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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FSTL1-USP10-Notch1 Signaling Axis Protects Against Cardiac Dysfunction Through Inhibition of Myocardial Fibrosis in Diabetic Mice

Yang

et al. 2021

Front. Cell Dev. Biol.

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The incidence of type 2 diabetes mellitus (T2DM) has been increasing globally, and T2DM patients are at an increased risk of major cardiac events such as myocardial infarction (MI). Nevertheless, the molecular mechanisms underlying MI injury in T2DM remain elusive. Ubiquitin-specific protease 10 (USP10) functions as a NICD1 (Notch1 receptor) deubiquitinase that fine-tunes the essential myocardial fibrosis regulator Notch signaling. Follistatin-like protein 1 (FSTL1) is a cardiokine with proven benefits in multiple pathological processes including cardiac fibrosis and insulin resistance. This study was designed to examine the roles of FSTL1/USP10/Notch1 signaling in MI-induced cardiac dysfunction in T2DM. High-fat-diet-treated, 8-week-old C57BL/6J mice and db/db T2DM mice were used. Intracardiac delivery of AAV9-FSTL1 was performed in T2DM mice following MI surgery with or without intraperitoneal injection of crenigacestat (LY3039478) and spautin-1. Our results demonstrated that FSTL1 improved cardiac function following MI under T2DM by reducing serum lactate dehydrogenase (LDH) and myocardial apoptosis as well as cardiac fibrosis. Further in vivo studies revealed that the protective role of FSTL1 against MI injury in T2DM was mediated by the activation of USP10/Notch1. FSTL1 protected cardiac fibroblasts (CFs) against DM-MI-induced cardiofibroblasts injury by suppressing the levels of fibrosis markers, and reducing LDH and MDA concentrations in a USP10/Notch1-dependent manner. In conclusion, FSTL1 treatment ameliorated cardiac dysfunction in MI with co-existent T2DM, possibly through inhibition of myocardial fibrosis and apoptosis by upregulating USP10/Notch1 signaling. This finding suggests the clinical relevance and therapeutic potential of FSTL1 in T2DM-associated MI and other cardiovascular diseases.

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“…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 play a role in tumour metastasis progression [ 5 ], including degradation of extracellular matrix [ 6 ], epithelial–mesenchymal transition [ 7 ], angiogenesis [ 8 , 9 ], circulating tumour cell behaviour [ 10 ], anoikis resistance [ 11 ] and so on. Proteasome and ubiquitin E3 ligase inhibitors and first-generation DUB inhibitors are now approaching clinical trials [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

USP12 promotes breast cancer angiogenesis by maintaining midkine stability

Sheng

Wei

et al. 2021

Cell Death Dis

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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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Deubiquitinase USP10 regulates Notch signaling in the endothelium

Cited by 70 publications

References 43 publications

Cooperation Between Cancer and Fibroblasts in Vascular Mimicry and N2-Type Neutrophil Recruitment via Notch2–Jagged1 Interaction in Lung Cancer

Cooperation Between Cancer and Fibroblasts in Vascular Mimicry and N2-Type Neutrophil Recruitment via Notch2–Jagged1 Interaction in Lung Cancer

FSTL1-USP10-Notch1 Signaling Axis Protects Against Cardiac Dysfunction Through Inhibition of Myocardial Fibrosis in Diabetic Mice

USP12 promotes breast cancer angiogenesis by maintaining midkine stability

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