Emerging Role of Deubiquitinating Enzymes (DUBs) in Melanoma Pathogenesis

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.

Nrf2 as a Therapeutic Target in the Resistance to Targeted Therapies in Melanoma

“…They can be grouped into five main classes: ubiquitin-specific proteases (USPs), the cysteine proteases ubiquitin C-terminal hydrolases (UCHs), ovarian tumor proteases (OTUs), the metalloproteases JAB1/MPN/MOV34 (JAMM), and the Machado-Joseph domain proteases (MJDs) [ 72 ]. Recently, the emerging role of DUBs in melanoma progression and the development of therapeutic resistance were highlighted [ 36 ]. DUB3 belongs to the USP17 gene family; it is highly expressed in cancer cell lines and has an established role in tumor proliferation [ 73 ].…”

“…Thus, it is very likely that post-translational mechanisms can account for the Nrf2 activation in melanoma [ 34 ]. Recently, the pivotal role of deubiquitinases (DUBs) as druggable targets in melanoma has been reported [ 35 , 36 ]. The specific DUB3 has been found to stabilize Nrf2, conferring chemotherapy resistance in cancer [ 26 , 31 ].…”

Programmed Death Ligand 1 Regulatory Crosstalk with Ubiquitination and Deubiquitination: Implications in Cancer Immunotherapy

“…DUBs are classified based on their catalytic mechanisms and structural features and encompass various superfamilies, including ubiquitin-specific protease (USP), ubiquitin C-terminal hydrolase (UCH), ovarian tumor protease (OTU), Machado–Josephin domain superfamily (MJD), and JAMMs (JAB1/MPN/Mov34) metalloproteases. These enzymes specifically cleave ubiquitin from ubiquitinated substrates to regulate crucial cellular processes [ 70 , 71 , 72 , 73 , 74 ].…”

Novel Therapeutic Targets in Melanoma

“…Considering that the upregulation of ECM proteins is a common mechanism in solid tumors that contributes to matrix stiffness, malignancy and metastasis, this work supports the clinical evaluation of TP-472 alone of more probably in combination with existing melanoma therapies. Ohanna and colleagues have chosen another attack angle and present an extensive review on the emerging role of deubiquitinating enzymes (DUBs) [6]. Interestingly, DUBs are involved in the pelorics aspect of tumorigenesis and aggressiveness, especially in melanoma, and could targeting existing pharmacological inhibitors to increase melanoma treatments and bypass resistance.…”