The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway

Zhao, Binghao; Schlesiger, Claudia; Masucci, Maria G.; Lindsten, Kristina

doi:10.1111/j.1582-4934.2009.00682.x

Cited by 44 publications

(36 citation statements)

References 51 publications

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“…Furthermore, USP4 has been shown to be a negative regulator of the canonical Wnt signal pathway. It is well known to have tumorigenesis activity (35). Thus, these data indicated that USP4 may act as a tumor suppressor.…”

Section: Discussionmentioning

confidence: 72%

Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis

Xing

Guo

et al. 2016

Cancer Research

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Ubiquitin specific protease 4 (USP4) is a deubiquitinating enzyme with key roles in the regulation of p53 and TGFb signaling, suggesting its importance in tumorigenesis. However, the mechanisms and regulatory roles of USP4 in cancer, including colorectal cancer, remain largely elusive. Here, we present the first evidence that USP4 regulates the growth, invasion, and metastasis of colorectal cancer. USP4 expression was significantly elevated in colorectal cancer tissues and was significantly associated with tumor size, differentiation, distant metastasis, and poor survival. Knockdown of USP4 diminished colorectal cancer cell growth, colony formation, migration, and invasion in vitro and metastasis in vivo. Importantly, we found that phosphatase of regenerating liver-3 (PRL-3) is indispensable for USP4-mediated oncogenic activity in colorectal cancer.Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination. This resulted in activation of Akt and reduction of E-cadherin, critical regulators of cancer cell growth and metastasis. Examination of clinical samples confirmed that USP4 expression positively correlates with PRL-3 protein expression, but not mRNA transcript levels. Taken together, our results demonstrate that aberrant expression of USP4 contributes to the development and progression of colorectal cancer and reveal a critical mechanism underlying USP4-mediated oncogenic activity. These observations suggest that the potential of harnessing proteolytic degradation processes for therapeutic manipulation may offer a much-needed new approach for improving colorectal cancer treatment strategies. Cancer Res; 76(1); 83-95. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 72%

Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis

Xing

Guo

et al. 2016

Cancer Research

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“…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%

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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“…USP4 has the capability to cleave free Lys-63 polyubiquitin chains (38). The free polyubiquitin chains synthesized by TRAF6 are direct activators for TAK1 (39).…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin-specific Protease 4 Mitigates Toll-like/Interleukin-1 Receptor Signaling and Regulates Innate Immune Activation

Zhou

Zhang

Dam

et al. 2012

Journal of Biological Chemistry

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Background:The TRAF6-mediated Toll-like receptor (TLR)/IL-1 receptor (IL-1R) pathway is essential for innate immune responses and immune homeostasis. Results: USP4 deubiquitinates Lys-63-linked polyubiquitination of TRAF6 and thereby prevents the TLR/IL-1R-induced activation of NF-B and AP-1 transcription factors and subsequent proinflammatory responses. Conclusion: USP4 plays an essential role in the negative regulation of the TLR/IL-1R signaling-mediated innate immune response. Significance: USP4 is an attractive new therapeutic target for modulation of innate immune responses.

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The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway

Cited by 44 publications

References 51 publications

Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis

Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Ubiquitin-specific Protease 4 Mitigates Toll-like/Interleukin-1 Receptor Signaling and Regulates Innate Immune Activation

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