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.
Highlights
Ubiquitination, one of the most conserved protein post-translational modifications, is controlled by the ubiquitin system, a dynamic multifaceted network involved in most aspects of eukaryotic biology
Using loss of function approaches, we demonstrated that FBXO32 silencing in melanoma cell lines induced a downregulation of CDK6, a cell cycle protein promoting proliferation, and an upregulation of SMAD7, an inhibitor of the TGF-β pathway linked to cell migration
These enzymes fall into two main categories: the cysteine proteases comprising the ubiquitin C-terminus hydrolases (UCHs), ubiquitin-specific proteases (USPs), ovarian tumor proteases (OTUs), Machado–Josephin domain proteases (MJDs), and the metalloprotease Jab1/MPN/Mov34 (JAMM) domain containing metalloisopeptidase [87]
Summary
Ubiquitination, one of the most conserved protein post-translational modifications, is controlled by the ubiquitin system, a dynamic multifaceted network involved in most aspects of eukaryotic biology. The ubiquitination process is well-known to play a key role in protein homeostasis through the control of 26S-mediated proteasome degradation, and includes nonproteolytic roles, such as receptor internalization, assembly of multiprotein complexes, inflammatory signaling, DNA damage repair, cell death, autophagy, or metabolism [1]. Many proteins, regulated by ubiquitination, control cellular processes relevant to tumorigenesis, such as the modulation of the activity of tumor promoters and suppressors. One of the best-known examples is the RING-type E3 ubiquitin ligase MDM2, a negative regulator of the p53 tumor suppressor [2]. Ubiquitination enzymes are considered potential therapeutic targets for cancers [3,4]. In cancer-relevant processes, and shed light on the therapeutic potential of the ubiquitin system [5].
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