Emerging role of DUBs in tumor metastasis and apoptosis: Therapeutic implication

He, Meiling; Zhou, Zhuan; Wu, George Y.; Chen, Qianming; Wan, Yong

doi:10.1016/j.pharmthera.2017.03.001

Cited by 68 publications

(42 citation statements)

References 150 publications

(153 reference statements)

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“…In contrast, the activation of HH signaling induced by the agonist purmorphamine (PM) results in enhanced USP37 gene expression that in turn stabilizes GLI1 ( Figure 5 A), and impacts on EMT in BCSBs [ 131 ]. These findings confirm the role of HH signaling in the maintenance of stem cells and EMT [ 132 , 133 ] and the implication of DUBs deregulations on these oncogenic processes [ 134 , 135 ]. Indeed, USP37 downregulation attenuates cell invasion and EMT markers expression by suppressing the HH pathway [ 131 ].…”

Section: Oncogenic Dubs Involved In the Regulation Of The Hh Pathwsupporting

confidence: 82%

DUBs Activating the Hedgehog Signaling Pathway: A Promising Therapeutic Target in Cancer

Bufalieri

Severini

Caimano

et al. 2020

Cancers

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The Hedgehog (HH) pathway governs cell proliferation and patterning during embryonic development and is involved in regeneration, homeostasis and stem cell maintenance in adult tissues. The activity of this signaling is finely modulated at multiple levels and its dysregulation contributes to the onset of several human cancers. Ubiquitylation is a coordinated post-translational modification that controls a wide range of cellular functions and signaling transduction pathways. It is mediated by a sequential enzymatic network, in which ubiquitin ligases (E3) and deubiquitylase (DUBs) proteins are the main actors. The dynamic balance of the activity of these enzymes dictates the abundance and the fate of cellular proteins, thus affecting both physiological and pathological processes. Several E3 ligases regulating the stability and activity of the key components of the HH pathway have been identified. Further, DUBs have emerged as novel players in HH signaling transduction, resulting as attractive and promising drug targets. Here, we review the HH-associated DUBs, discussing the consequences of deubiquitylation on the maintenance of the HH pathway activity and its implication in tumorigenesis. We also report the recent progress in the development of selective inhibitors for the DUBs here reviewed, with potential applications for the treatment of HH-related tumors.

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Section: Oncogenic Dubs Involved In the Regulation Of The Hh Pathwsupporting

confidence: 82%

DUBs Activating the Hedgehog Signaling Pathway: A Promising Therapeutic Target in Cancer

Bufalieri

Severini

Caimano

et al. 2020

Cancers

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“…Deubiquitinating enzymes (DUBs) can prevent ubiquitin-mediated degradation of target proteins [ 12 ]. Importantly, dysregulated DUBs expression is frequently associated with the tumorigenesis process, specifically cell self-renewal, apoptosis and EMT [ 13 , 14 ]. It has been confirmed that DUBs are essential for the regulation of stem cell-related markers and controlling various steps of metastatic progression, including invasion, dissemination and eventual metastasis to distant organs [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity

Qin

Feng

et al. 2018

J Exp Clin Cancer Res

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BackgroundRecent studies have indicated that deubiquitinating enzymes (DUBs) are related to the stem-cell pathway network and chemo-resistance in cancer. Ubiquitin-specific peptidase 37 (USP37), a novel DUB, was identified to be a potential factor associated with tumor progression. However, the biological functions of USP37 in breast cancer remain unclear.MethodsThe distribution of USP37 expression in breast cancer and the correlation between USP37 expression and the overall survival rate were detected by The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) was utilized to evaluate potential mechanism of USP37 in breast cancer. The USP37 expression in breast cancer tissues and breast cancer cell lines were detected by immunohistochemistry and western blotting. Sorting of breast cancer stem cells (BCSCs) were by using MACS assay. In vitro and in vivo assays were performed to examine the biological functions of USP37 in breast cancer cells. MG132, CHX chase, immunofluorescence staining and co-immunoprecipitation assays were used to test the interaction between USP37 and Gli-1.ResultsBioinformatics analysis demonstrated that USP37 gene was elevated in breast cancer tissues and its overexpression was strongly correlated with the increased mortality rate. GSEA analysis showed that USP37 expression was positively associated with cell growth and metastasis while negatively related to cell apoptosis in the TCGA breast cancer samples. USP37 expression was elevated in breast cancer tissues and breast cancer cell lines. Moreover, we also detected that USP37 was overexpressed in BCSCs. USP37 regulated the ability of cell invasion, epithelial-mesenchymal transition (EMT), stemness and cisplatin sensitivity in breast cancer cell lines. Additionally, USP37 knockdown inhibited tumorigenicity and increased anticancer effect of cisplatin in vivo. Knockdown of USP37 significantly decreased hedgehog (Hh) pathway components Smo and Gli-1. Gli-1 was stabilized by USP37 and they interacted with each other. Further studies indicated that USP37 knockdown could inhibit the stemness, cell invasion and EMT in breast cancer via downregulation of Hh pathway.ConclusionsThese findings reveal that USP37 is highly expressed in BCSCs and is correlated with poor prognosis in breast cancer patients. USP37 can regulate the stemness, cell invasion and EMT via Hh pathway, and decreased USP37 confers sensitivity to cisplatin in breast cancer cells. USP37 is required for the regulation of breast cancer progression, as well as a critical target for clinical treatment of breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0934-9) contains supplementary material, which is available to authorized users.

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“…Mechanistically, our research proves that USP15 directly deubiquitinates EIF4A1 to promote wound healing in keratinocytes. Because USP15 harbors druggable enzymatic activity as a member of the DUBs, it is considered a potential therapeutic target with vital clinical applications ( He et al, 2017 ). Recombinant DUBs or DUB-based virus-related therapy could further be applied to accelerate re-epithelialization, whereas small molecule inhibitors that target DUBs may become a promising intervention for cutaneous overhealing-associated diseases, such as hypertrophic scars and keloids ( Lee et al, 2010 ; Piao et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

USP15 Enhances Re-epithelialization Through Deubiquitinating EIF4A1 During Cutaneous Wound Repair

Zhao

Huang

Zhang

et al. 2020

Front. Cell Dev. Biol.

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Re-epithelialization is a fundamental process in wound healing that involves various cytokines and cells during cutaneous barrier reconstruction. Ubiquitin-specific peptidase 15 ( USP15 ), an important member of the deubiquitinating enzymes (DUBs), removes ubiquitin chains from target proteins and maintains protein stability. However, the dynamic role of USP15 in epithelialization remains unclear. We aimed to investigate the regulatory function of USP15 in re-epithelialization. An excisional wound splinting model was established to evaluate the re-epithelialization rate in Usp15 knockout (KO) mice. Coimmunoprecipitation (Co-IP) and mass spectrum analyses were performed to identify USP15-interacting proteins. RNA-sequencing was performed for transcriptome analysis in keratinocytes and uploaded into NODE database ( http://www.biosino.org/node , accession numbers: OEP000770 and OEP000763 ). First, a significant delay in epithelialization was observed in the Usp15 KO mice. Moreover, inhibition of cell migration and proliferation was observed in the USP15-silenced keratinocytes (HaCaTs). Moreover, we revealed for the first time that USP15 could interact with eukaryotic initiation factor 4A-1 (EIF4A1), thereby promoting translational efficacy in keratinocytes, which is essential for keratinocyte proliferation and migration. Conclusively, the USP15-EIF4A1 complex significantly accelerated re-epithelialization in wound healing. These observations helped elucidate the function and mechanisms of USP15 in modulating re-epithelialization in wound healing, providing a promising target for refractory wound treatment.

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Emerging role of DUBs in tumor metastasis and apoptosis: Therapeutic implication

Cited by 68 publications

References 150 publications

DUBs Activating the Hedgehog Signaling Pathway: A Promising Therapeutic Target in Cancer

DUBs Activating the Hedgehog Signaling Pathway: A Promising Therapeutic Target in Cancer

Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity

USP15 Enhances Re-epithelialization Through Deubiquitinating EIF4A1 During Cutaneous Wound Repair

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