Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Abstract

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.

A PAK5–DNPEP–USP4 axis dictates breast cancer growth and metastasis

“…Since its discovery, USP4 has been well characterized as a tumor promotor in multiple cancer types. For example, USP4 suppresses stress‐induced cell apoptosis and facilitates tumor metastasis in melanoma . USP4 promotes the suppressive function of Treg cells by interacting with and stabilizing interferon regulatory factor 8 (IRF8) .…”

“…See also Supporting Information Figure S4. [Color figure can be viewed at wileyonlinelibrary.com] facilitates tumor metastasis in melanoma. 26 USP4 promotes the suppressive function of Treg cells by interacting with and stabilizing interferon regulatory factor 8 (IRF8). 27 Furthermore, USP4 targets transforming growth factor-β-activated kinase 1 (TAK1) to regulate tumor necrosis factor-α (TNFα)-induced NF-κB activation.…”

Epigenetic Silencing of Ubiquitin Specific Protease 4 by Snail1 Contributes to Macrophage-Dependent Inflammation and Therapeutic Resistance in Lung Cancer

“…In tissue samples from lung cancer patients, decreased expression of USP4 was associated with advanced cancer stage. In line with these results, a protective effect of USP4 was reported in lung adenocarcinoma and breast cancer patients, although distinct effects of USP4 have been reported for other cancer types [48][49][50][51][52][53]. For instance, expression of USP4 was downregulated in lung adenocarcinoma, and low USP4 expression was associated with poor overall survival and recurrence-free survival [48].…”

“…Moreover, expression of this DUB inhibited cell proliferation in vitro and suppressed tumor growth in an animal model [49]. In contrast, increased expression of USP4 was found in tissue samples from hepatocellular carcinoma, melanoma, esophageal cancer, and colorectal cancer, and USP4 was shown to be oncogenic in these cancer cells [50][51][52][53]. These results suggest that the expression and tumor promoting effect of USP4 may be cancer type specific and that aberrant expression of USP4 can either increase or decrease tumorigenesis depend on the different cell contexts.…”

Systematical identifications of prognostic meaningful lung adenocarcinoma subtypes and the underlying mutational and expressional characters

“…USP4 is a deubiquitinating enzyme which may inhibit p53 by deubiquitinating an important p53 ubiquitin ligase ARF-BP1 [35]. Correspondingly, many studies have identified the oncogene effects of USP4 [36]. Here, on the contrary, we found that higher expressions of USP4 in LUAD may lead to better prognosis.…”