Ubiquitin ligases in cancer: Functions and clinical potentials

Abstract

Ubiquitylation, a highly regulated post-translational modification, controls many cellular pathways that are critical to cell homeostasis. Ubiquitin ligases recruit substrates and promote ubiquitin transfer onto targets, inducing proteasomal degradation or non-degradative signaling. Accumulating evidence highlights the critical role of dysregulated ubiquitin ligases in processes associated with the initiation and progression of cancer. Depending on the substrate specificity and biological context, a ubiquitin ligase can act either as a tumor promoter or as a tumor suppressor. In this review, we focus on the regulatory roles of ubiquitin ligases and how perturbations of their functions contribute to cancer pathogenesis. We also briefly discuss current strategies for targeting or exploiting ubiquitin ligases for cancer therapy.

Figure 1.. Deregulation of E3-mediated ubiquitylation in cancer.

The illustration shows different modes of E3 deregulation, with well-established examples listed. Most deregulations in E3s arise as a consequence of genetic or epigenetic alterations, which can affect the abundance and/or activity of their substrates. For example, deletions, mutations, or promoter methylations can inactivate E3s that normally function as tumor suppressors, and lead to the overexpression of oncoprotein substrates (e.g., c-Myc, cyclin E, and ERG). Alternatively, overexpression of E3s (e.g., through gene amplification of MDM2 and SKP2 loci) that target tumor suppressors (p53 and p27, respectively) can promote tumor formation. In addition, mutations in the substrates, which enable them to escape the recognition by E3s can lead to their accumulation.

Figure 2.. E3s in the regulation of the hallmarks of cancer

E3s are hubs of many cellular processes, including those playing key roles in cell proliferation, cell cycle, the DNA damage response, apoptosis, metabolism, metastasis, angiogenesis, immune checkpoint, and viral infections. Representative E3s with their best-defined substrates in these biological processes are listed.

Figure 3:. Therapeutic strategies targeting E3s

a. E3 inhibitors. Small molecules that either inhibit the activity of E3, or block its interaction with substrates. b. Targeted protein degradation. PROteolysis TArgeting Chimeras (PROTACs) are bifunctional molecules simultaneously engage a protein of interest and a E3, to form a ternary complex and enable the E3 to mediate the ubiquitylation and subsequent degradation of the neo-substrate. Molecule glues are small compounds that redirect E3s to neo-substrates. They can be either natural compounds (for example, plant hormones), or synthetic compounds (such as IMiDs and indisulam). The induced proximity by the small molecule leads to substrate ubiquitylation by E3s and subsequent proteasomal degradation. Molecule glues do not require high affinity on both the E3 and the neo-substrate, eliminating the need for at least one of the two ligand-binding pockets required for PROTACs