Emerging Role of Deubiquitinating Enzymes (DUBs) in Melanoma Pathogenesis

SIMPLE SUMMARY: Metastatic melanoma is one of the most aggressive skin tumors with a poor prognosis. Despite the efficacy of immunotherapy and targeted therapies, advanced melanoma patients are often refractory to treatments and have high rates of relapse and death. A major challenge is to identify and understand the mechanisms associated with melanoma development and resistance to gold-standard therapies. Thus, new therapeutic strategies are needed. Ubiquitination is a post-translational modification that plays a crucial role in various cellular biological activities and participates in cancer pathogenesis, including melanoma. Here, we report on the deubiquitination enzymes (DUBs) and their ubiquitin-modified substrates and signaling pathways involved in melanoma progression. ABSTRACT: Metastatic melanoma is the leading cause of death from skin cancer. Therapies targeting the BRAF oncogenic pathway and immunotherapies show remarkable clinical efficacy. However, these treatments are limited to subgroups of patients and relapse is common. Overall, the majority of patients require additional treatments, justifying the development of new therapeutic strategies. Non-genetic and genetic alterations are considered to be important drivers of cellular adaptation mechanisms to current therapies and disease relapse. Importantly, modification of the overall proteome in response to non-genetic and genetic events supports major cellular changes that are required for the survival, proliferation, and migration of melanoma cells. However, the mechanisms underlying these adaptive responses remain to be investigated. The major contributor to proteome remodeling involves the ubiquitin pathway, ubiquitinating enzymes, and ubiquitin-specific proteases also known as DeUBiquitinases (DUBs). In this review, we summarize the current knowledge regarding the nature and roles of the DUBs recently identified in melanoma progression and therapeutic resistance and discuss their potential as novel sources of vulnerability for melanoma therapy.