An Update on the Role of Ubiquitination in Melanoma Development and Therapies

Abstract

The ubiquitination system plays a critical role in regulation of large array of biological processes and its alteration has been involved in the pathogenesis of cancers, among them cutaneous melanoma, which is responsible for the most deaths from skin cancers. Over the last decades, targeted therapies and immunotherapies became the standard therapeutic strategies for advanced melanomas. However, despite these breakthroughs, the prognosis of metastatic melanoma patients remains unoptimistic, mainly due to intrinsic or acquired resistances. Many avenues of research have been investigated to find new therapeutic targets for improving patient outcomes. Because of the pleiotropic functions of ubiquitination, and because each step of ubiquitination is amenable to pharmacological targeting, much attention has been paid to the role of this process in melanoma development and resistance to therapies. In this review, we summarize the latest data on ubiquitination and discuss the possible impacts on melanoma treatments.

USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K

“…Loss of USP28 in tumour cells is favoured as it results in TP53 protein destabilization, thereby establishing a switch of cell fate, from apoptosis towards mitosis. Hence, USP28 functions as a tumour suppressor in melanoma [55]. In line with these reports, we could not detect a correlation between USP28 and BRAF expression in human skin cancer samples.…”

USP28 enables oncogenic transformation of respiratory cells and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K

“…Loss of USP28 in tumour cells is favored as it results in TP53 protein destabilization, thereby establishing a switch of cell fate, from apoptosis towards mitosis. Hence, USP28 functions as a tumour suppressor in melanoma(41). In line with these reports, we could not detect a correlation between USP28 and BRAF expression in human skin cancer samples.…”

NEDD4 E3 ubiquitin protein ligase serves an important role in cutaneous melanoma occurrence and development

“…Over the past few years, studies have reported that NEDD4 serves an essential role in tumor development (33)(34)(35)(36). For example, relevant research findings have shown that abnormal expression of NEDD4 is closely associated with the bioactivity and prognosis of tumors (38)(39)(40)(41).…”

“…Consequently, the confirmational changes to E3 ubiquitin-ligating enzymes, and E2 (which carries ubiquitin), promote entry to the E3-substrate complex, such that the substrate can be ubiquitinated ( 32 ). Numerous studies have reported that neddylation not only enables a significant increase in the ubiquitination efficiency of proteins to be degraded, but also promotes the degradation of these proteins by the 26S proteasome ( 33 , 34 ).…”