E3 ubiquitin ligases as drug targets and prognostic biomarkers in melanoma

Abstract

Melanomas are highly proliferative and invasive, and are most frequently metastatic. Despite many advances in cancer treatment over the last several decades, the prognosis for patients with advanced melanoma remains poor. New treatment methods and strategies are necessary. The main hallmark of cancer is uncontrolled cellular proliferation with alterations in the expression of proteins. Ubiquitin and ubiquitin-related proteins posttranslationally modify proteins and thereby alter their functions. The ubiquitination process is involved in various physiological responses, including cell growth, cell death, and DNA damage repair. E3 ligases, the most specific enzymes of ubiquitination system, participate in the turnover of many key regulatory proteins and in the development of cancer. E3 ligases are of interest as drug targets for their ability to regulate proteins stability and functions. Compared to the general proteasome inhibitor bortezomib, which blocks the entire protein degradation, drugs that target a particular E3 ligase are expected to have better selectivity with less associated toxicity. Components of different E3 ligases complexes (FBW7, MDM2, RBX1/ROC1, RBX2/ROC2, cullins and many others) are known as oncogenes or tumor suppressors in melanomagenesis. These proteins participate in regulation of different cellular pathways and such important proteins in cancer development as p53 and Notch. In this review we summarized published data on the role of known E3 ligases in the development of melanoma and discuss the inhibitors of E3 ligases as a novel approach for the treatment of malignant melanomas.

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

“…Substrate recognition of E3s is essential for efficient and selective target degradation and is mediated by a variety of well-defined peptide motifs known as degrons (Varshavsky, 1991; Lucas and Ciulli, 2017). Due to their implication in numerous pathophysiological conditions and their ability to regulate protein function and stability, E3s themselves have emerged as drug targets (Kirkin and Dikic, 2011; Lipkowitz and Weissman, 2011; Bielskiene et al, 2015). …”

Proteasome‐mediated proteostasis: Novel medicinal and pharmacological strategies for diseases

“…E3 ubiquitin ligases possess an E2‐binding domain and based on their mechanism of ubiquitin transfer to the substrate protein, they are classified in different families . Participation of E3 ubiquitin ligases in various cellular mechanisms makes them an attractive choice as drug targets in different diseases . But still several questions on the mechanism and functions of E3 ubiquitin ligases remain unaddressed and need further consideration.…”

E3 Ubiquitin Ligases Neurobiological Mechanisms: Development to Degeneration

“…CUL4B mutation may result in X-linked mental retardation (Zou et al, 2007); whereas TRIM family of E3 ubiquitin ligases have been implicated in several developmental disorders, e.g., TRIM50 in Williams–Beuren syndrome (Micale et al, 2008), Midline 1 (MID1) in Opitz syndrome (Quaderi et al, 1997), and TRIM37 in Mulibrey Nanism (Kallijarvi et al, 2002). As discussed above, most of the substrates of E3 ubiquitin ligases are regulatory proteins involved in different signaling pathways, controlling cell cycle progression, cellular metabolism, apoptosis, etc., and hence may impact development and growth of organism (Bielskiene et al, 2015). Thus, disturbances caused in the ubiquitylation mechanism due to impairment in E3 ubiquitin ligases functionalities may lead to different kinds of abnormal conditions, developmental disorders, and embryonic lethality (Huang and Dixit, 2016).…”