Author: Camille Jessica Cunanan
Skin cancer is the most common form of cancer in the United States, surpassing cancers of the breasts and lungs (1). Melanoma is the deadliest form of skin cancer, causing an average of 178,000 diagnoses and 9,700 deaths in the United States each year (1)(2). Contrary to popular belief, melanoma not only occurs in the skin, but can also develop on the eyes, scalp, nails, feet, and mouth (2). Current innovative therapies for melanoma include inhibitors of enzymes, BRAF and MEK, in which defective forms of the enzymes have produced oncogenic effects (3). In addition, cisplatin, a chemotherapeutic agent, has been shown to induce DNA damage in cancer cells, obstructing tumorigenesis. Although BRAF/MEK inhibitors and cisplatin have proposed revolutionary advances for the fate of melanoma patients, such therapies have shown to be ineffective in aggressive metastatic forms of melanoma. The survival rate of melanoma after the occurrence of metastasis remains to be <20%, emphasizing the importance of unraveling the underlying mechanism of melanoma pathogenesis and improving the efficiency of therapeutics for the disease (2).
In a recent publication titled, “Up-regulated deubiquitinase USP4 plays an oncogenic role in melanoma,” Guo et al. discover the contribution of USP4 in melanoma pathogenesis, providing a starting block for developing more effective treatments for melanoma. The authors articulate the effects of the expression of the deubiquitinase, USP4, on melanoma tissues. They begin their article by explaining the roles of ubiquitinases and deubiquitnases in cancer cell proliferation, particularly on tumor protein, p53. Guo et al. then validate their findings, with studies that demonstrate that upregulated USP4 in melanoma cells plays an oncogenic role by simultaneously suppressing stress-induced cell apoptosis and facilitating tumor metastasis.
Ubiquitination is an important post-translational modification and participates in a wide range of processes, including metabolism, cell proliferation, inflammatory response, and autophagy. Ubiquitin modification is regulated by ubiquitin-conjugating and ubiquitin-deconjugating enzymes (3). Ubiqutination-related genes are frequently identified and participate in melanoma tumorigenesis, in addition to ubiquitin-dependent signaling pathways critical to development, demonstrating its vital pathogenic role in melanoma.
The mechanisms of deubuitinating enzymes and their roles in pathogenesis, however, are less understood. Deubuitinating enzymes mediate the removal and processing of ubiquitin and consists of ubiquitin-specific proteases (USPs). USP4 has been linked to cancer associated DNA-repair and p53 stability. Deubiquitination and stabilization of oncogenes by overexpression of USP4 has been characterized in certain cancers. Additionally, USP4 has been found to have a tumor-suppressive role by inhibiting cell proliferation or promoting cell apoptosis. Such information has suggested to the impact of USP4 on cancer biology and prompted the work conducted by Guo et al. in melanoma cell lines and tissues.
The most influential discovery made by the authors is that USP4 expression is significantly upregulated in melanoma, suggesting that USP4 may act as an oncogene. Guo et al. studied the mRNA and protein level of USP4 in a panel of melanoma cell lines at different clinical stages (WM793B, WM35 at primary stage and A2058, A375, 451Lu at metastatic stage) and in normal human melanocytes. Not only did they find that USP4 expression was largely increased in melanoma cells (Figure 1A), but real-time quantitative reverse transcription-PCR assays and immunofluorescent staining also revealed that the mRNA level of USP4 was prominently up-regulated in melanoma cell lines. Moreover, USP4 expression was higher in metastatic cells than in primary cells (Figure 1B and Figure 1C). Additionally, intensity of USP4 in metastatic melanoma tissues was markedly higher than in primary ones (Figure 1D). The authors then compared their results to The Cancer Genome Atlas skin cutaneous database and found that mRNA expression of USP4 was significantly higher in metastatic melanoma compared with that in primary melanoma in the database, further confirming their results in both melanoma cell lines and tissues (Figure 1E).
The ability to overcome stress-induced apoptosis is characteristic of tumor cells. Cisplatin is a conventional chemotherapeutic that induces DNA damage and affects proliferation; however, intrinsic pro-survival signaling present in cancer cells destroys the efficacy of cisplatin and can induce tolerance and tumor development in melanoma. In this article, Guo et al. demonstrate that USP4 protects melanoma cells from cisplatin-induced apoptosis in a p53-dependent manner. The authors performed flow cytometry analysis to determine the cell apoptotic rate of cisplatin-treated melanoma cells and found that cisplatin treatment was able to induce prominent cell apoptosis in melanoma. This suggests that USP4 is a critical pro-survival molecule in response to cisplatin treatment. When Guo et al. measured the expression of apoptosis-associated molecules, they found upregulated expression in cisplatin-treated melanoma cells with USP4 knockout. Such results suggest that USP4 has the ability to obstruct cisplatin-induced apoptosis in melanoma cells, thus inducing tolerance to cisplatin treatment.
Guo et al. also studied whether USP4 has an influence on migration and invasion of melanoma cells. Through transwell invasion and migration assays, the authors found that knockdown of USP4 remarkably reduced both the invasive and migratory capacity of melanoma cells. Such findings led to the conclusions that in addition to the anti-apoptotic effect in response to cisplatin, USP4 was also important in promoting the invasion and migration of melanoma cells.
The authors further investigated the role of USP4 on melanoma epithelial-mesenchymal transition (EMT). EMT enhances a tumor cell metastatic ability and is characterized by upregulated N-cadherin and downregulated E-cadherin expression (5). Knockdown of USP4 induced drastic downregulation of N-cadherin and upregulation of E-cadherin, indicating that USP4 deficiency could reverse the process of EMT. Conclusively, the data presented by Guo et al. demonstrates that USP4 promotes melanoma cell migration and invasion by promoting EMT.
The findings reported by Guo et al. provide justification that USP4 can serve as a drug target by demonstrating that USP4 is significantly increased in melanoma and plays an oncogenic role by simultaneously inhibiting stress-induced cell apoptosis and promoting tumor metastasis. The process of ubiquitnation is one of the most evolutionarily conserved protein post-translational modifications that can contribute to preventing or causing certain diseases like that of cancer (6). Understanding the pathways of ubiquitination and revealing the roles they have on disease progression is imperative to developing efficacious therapeutics for diseases such as cancer. Therefore, targeting USP4 and other ubiquitin-related enzymes can potentially be a therapeutic target for melanoma treatment.
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(2) Guo, W.; Ma, J.; Pei, T.; Zhao, T.; Guo, S.; Yi, X.; Liu, Y.; Wang, S.; Zhu, G.; Jian, Z.; et al. Up-Regulated Deubiquitinase USP4 Plays an Oncogenic Role in Melanoma. J. Cell. Mol. Med. 2018.
(3) Eroglu, Z.; Ribas, A. Combination Therapy with BRAF and MEK Inhibitors for Melanoma: Latest Evidence and Place in Therapy. Ther Adv Med Oncol 2016, 8 (1), 48–56.
(4) Ma J, Guo W, Li C. Ubiquitination in melanoma pathogenesis and treatment. Cancer Med 2017;6:1362-1377.
(5) Ye X, Weinberg RA. Epithelial-mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol. 2015;25:675-686.
(6) Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat Med. 2014;20:1242-1253.
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