USP8 is a Novel Therapeutic Target in Melanoma Through Regulating Receptor Tyrosine Kinase Levels

Abstract

The hyperactivation of receptor tyrosine kinase (RTK)-mediated pathways plays an important role in melanoma progression and resistance to therapy. The ubiquitinspecific protease 8 (USP8) is a deubiquitinating enzyme and its inhibition induces degradation of RTKs. This work explored the expression and role of USP8 in melanoma. Methods: ELISA and qPCR were performed to assess USP8 expression in melanoma tissues and cells, as well as their normal counterparts. Cellular proliferation, migration and apoptosis assays were performed to determine USP8 functions in three melanoma cell lines. Western blot was performed to analyze RTK signaling in melanoma cells after USP8 inhibition. Results: mRNA and protein level of USP8 were higher in melanoma cells than normal melanocytes. Higher USP8 expression was also found in tumors in the majority of melanoma patients. USP8 expression was not associated with clinicopathological features, such as age, disease stage, histology, ulceration and BRAF status. Functional analysis demonstrated that USP8 overexpression promoted melanoma cell activities and alleviated the inhibitory effects of therapeutic drugs. In contrast, USP8 knockdown suppressed melanoma cell growth, survival and migration, and augmented the inhibitory effects of therapeutic drugs. Mechanism studies revealed that USP8 inhibition remarkably reduced the expression level of multiple oncogenic RTKs, including c-Met, Kit, EGFR and GPCR. Consistently, RTKmediated downstream pathways were disrupted in USP8-depleted cells, leading to the increased level of pro-apoptotic proteins and decreased level of anti-apoptotic proteins. Conclusion: Inhibition of USP8 activity is a novel sensitizing strategy to overcome therapy resistance in melanoma.

Canine Oral Melanoma Genomic and Transcriptomic Study Defines Two Molecular Subgroups with Different Therapeutical Targets

“…Moreover, a high expression of TRPM7, USP8, GABPB1, or SPPL2A was shown to be associated with shorter survival times in cutaneous melanomas (Log-rank TRPM7, p -value = 0.005; Log-rank USP8, p -value = 0.017; Log-rank GABPB1, p -value = 0.019; and Log-rank GABPB1, p -value = 0.022) ( , accessed on 1 July 2021). Interestingly, USP8 knockdown suppressed cell growth, survival, and migration in cutaneous melanoma [ 75 ]. In addition, TRPM7 expression levels have been shown to be associated with an invasive behavior and metastatic potential in cutaneous melanoma cell line [ 76 ] and is also expected to act as a protector in both melanocyte physiology and in melanoma cells [ 77 ].…”

A Proteomics Approach Identifies RREB1 as a Crucial Molecular Target of Imidazo–Pyrazole Treatment in SKMEL-28 Melanoma Cells

“…Also, we can find different DEPs contributing to these biological processes. The more interesting ones, confirmed by the bibliography on melanoma, are as follows: USP15 [ 23 ], TIPIN [ 24 ], TMC5 [ 25 ], TYMP [ 26 ], USP19 [ 27 ], USP8 [ 28 ], and TFAP2B [ 29 ]. At 48 h ( Figure 1 B), autophagy was found to be the most important BP, which is a crucial component of the cellular adaptive stress response.…”

Targeting USP8 Inhibits O‐GlcNAcylation of SLC7A11 to Promote Ferroptosis of Hepatocellular Carcinoma via Stabilization of OGT

“…USP8 expression is frequently upregulated in various types of cancer and related to poor prognosis, [43] including melanoma, gastric cancer, cholangiocarcinoma, breast cancer, and lung cancer. [44][45][46][47][48] High expression of USP8 is usually associated with the high proliferation and metastasis abilities of tumors. [49] It is reported that USP8 decreases the efficacy of anti-PD-L1/PD-1 immunotherapy via reshaping an inflamed tumor microenvironment (TME).…”