Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma

Hwang, Su Jin; Lee, Hye Won; Kim, Hye Ree; Hong, Liu; Shin, Chang Hoon; Yun, Sun-Il; Lee, Dong Heon; Kim, Duk-Hwan; Kim, Kyeong Kyu; Joo, Kyeung Min; Kim, Hyeon Ho

doi:10.1038/srep21596

Cited by 38 publications

(49 citation statements)

References 40 publications

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“…USP4 has been greatly implicated in regulating tumour metastasis in breast cancer, lung cancer and colorectal cancer 19, 33, 35, 36. Notably, the loss of E‐cadherin expression accounted for USP4‐mediated augmentation of tumour metastatic capacity in all of these cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, Wnt signalling and TGF‐β signalling are 2 critical pro‐metastatic signalling pathways in various cancers with the positively regulatory impact on EMT, including melanoma 37. Several lines of evidence have revealed that USP4 was tightly associated with these 2 canonical pathways 33, 36, 38. Specifically, USP4 could directly interact with TGF‐β type I receptor (TRI) and stabilize TRI levels at the plasma membrane though its deubiquitinating activity, thereby maintaining the sustained activation of TGF‐β signalling 33.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, USP4 could directly interact with TGF‐β type I receptor (TRI) and stabilize TRI levels at the plasma membrane though its deubiquitinating activity, thereby maintaining the sustained activation of TGF‐β signalling 33. In addition, up‐regulated USP4 expression contributed to Wnt activation by interacting and stabilizing different components of Wnt signalling, including β‐catenin, Nemo like kinase (Nlk) and T‐cell factor 4 (TCF4) 36, 38. Therefore, the facilitation of EMT and tumour metastasis by USP4 in melanoma may be also associated with the activation of TGF‐β and Wnt signalling, and this speculation needs to be further clarified.…”

Section: Discussionmentioning

confidence: 99%

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Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Guo

Pei

et al. 2018

J Cellular Molecular Medi

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Melanoma is the most malignant skin cancer with increasing incidence worldwide. Although innovative therapies such as BRAF inhibitor and immune checkpoint inhibitor have gained remarkable advances, metastatic melanoma remains an incurable disease for its notorious aggressiveness. Therefore, further clarification of the underlying mechanism of melanoma pathogenesis is critical for the improvement of melanoma therapy. Ubiquitination is an important regulatory event for cancer hallmarks and melanoma development, and the deubiquitinating enzymes including ubiquitin‐specific peptidase (USP) families are greatly implicated in modulating cancer biology. Herein, we first found that the expression of the deubiquitinase USP4 was significantly up‐regulated in melanoma tissues and cell lines. Furthermore, although USP4 knockdown had little impact on melanoma cell proliferation, it could increase the sensitivity to DNA damage agent cisplatin. We subsequently showed that USP4 regulated cisplatin‐induced cell apoptosis via p53 signalling. More importantly, USP4 could accentuate the invasive and migratory capacity of melanoma cells by promoting epithelial‐mesenchymal transition. Altogether, our results demonstrate that the up‐regulated USP4 plays an oncogenic role in melanoma by simultaneously suppressing stress‐induced cell apoptosis and facilitating tumour metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Guo

Pei

et al. 2018

J Cellular Molecular Medi

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“…Stabilization of PRL-3 resulted in activation of Akt and reduction of E-cadherin. Besides, USP4 was also found to be highly expressed in brain metastatic lung adenocarcinoma PC14PE6/LvBr4 cell lines as a β-catenin-specific deubiquitinating enzyme, involved in the increased stability of β-catenin protein (Hwang et al, 2016). Several reports revealed that some DUBs were involved in EMT event but the identities of the substrates remain unclear.…”

Section: Dubs In Regulation Of Critical Steps In Tumor Metastasismentioning

confidence: 99%

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

Zhou

et al. 2017

Pharmacology & Therapeutics

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Malfunction of ubiquitin-proteasome system is tightly linked to tumor formation and tumor metastasis. Targeting the ubiquitin-pathway provides a new strategy for anti-cancer therapy. Despite the parts played by ubiquitin modifiers, removal of ubiquitin from the functional proteins by the deubiquitinating enzymes (DUBs) plays an important role in governing the multiple steps of the metastatic cascade, including local invasion, dissemination, and eventual colonization of the tumor to distant organs. Both deregulated ubiquitination and deubiquitination could lead to dysregulation of various critical events and pathways such as apoptosis and epithelial-mesenchymal transition (EMT). Recent TCGA study has further revealed the connection between mutations of DUBs and various types of tumors. In addition, emerging drug design targeting DUBs provides a new strategy for anti-cancer therapy. In this review, we will summarize the role of deubiquitination and highlight the recent discoveries of DUBs with regards to multiple metastatic events including anti-apoptosis pathway and EMT. We will further discuss the regulation of deubiquitination as a novel strategy for anti-cancer therapy.

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“…86 We demonstrate here that both USP17 and USP4 are expressed at higher levels in breast and lung cancer cell lines compared to normal cells. Importantly, HAS2 was coexpressed in a similar pattern in the malignant cell lines, suggesting a correlation between HAS2, USP17 and USP4 protein levels.…”

Section: Discussionmentioning

confidence: 59%

The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function

Mehić

Hebestreit

et al. 2017

Oncogenesis

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The levels of hyaluronan, a ubiquitous glycosaminoglycan prominent in the extracellular matrix, is balanced through the actions of hyaluronan-synthesizing enzymes (HAS1, 2 and 3) and degrading hyaluronidases (Hyal 1, 2, 3 and PH20). Hyaluronan accumulates in rapidly remodeling tissues, such as breast cancer, due to deregulated expression of the HAS2 gene and/or alterations of HAS2 activity. The activity of HAS2 is regulated by post-translational modifications, including ubiquitination. In order to identify deubiquitinating enzymes (DUBs) that are involved in de-ubiquitination of HAS2, a complementary (cDNA) library of 69 Flag-HA-tagged human DUBs cloned into retroviral vectors was screened in human embryonic kidney (HEK) 293T cells for their ability to de-ubiquitinate myc-tagged HAS2. Several DUBs were found to decrease the ubiquitination of 6myc-HAS2, among which, the most effective were USP17 and USP4. USP17 efficiently removed polyubiquitination, whereas USP4 preferentially removed monoubiquitination of 6myc-HAS2. Co-immunoprecipitation studies revealed interactions between HAS2 and USP17, as well as between HAS2 and USP4, in membrane preparations of HEK293T cells. USP17 significantly stabilized 6myc-HAS2 protein levels, whereas USP4 did not. The silencing of USP17 led to decreased hyaluronan production, whereas the suppression of USP4 increased hyaluronan synthesis. Importantly, high levels of USP17 and HAS2 were detected in a panel of cancer cell lines compared to normal cells, and immunohistochemical stainings revealed higher expression of USP17 and HAS2 in tissues of lung cancer patients compared to normal tissue. In conclusion, USP17 and USP4 differently affect HAS2 ubiquitination, and the stability and function of HAS2.

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Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma

Cited by 38 publications

References 40 publications

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

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

The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function

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