Review article
Ubiquitination: Friend and foe in cancer

https://doi.org/10.1016/j.biocel.2018.06.001Get rights and content

Abstract

Dynamic modulation and posttranslational modification of proteins are tightly controlled biological processes that occur in response to physiological cues. One such dynamic modulation is ubiquitination, which marks proteins for degradation via the proteasome, altering their localization, affecting their activity, and promoting or interfering with protein interactions. Hence, ubiquitination is crucial for a plethora of physiological processes, including cell survival, differentiation and innate and adaptive immunity. Similar to kinases, components of the ubiquitination system are often deregulated, leading to a variety of diseases, such as cancer and neurodegenerative disorders. In a context-dependent manner, ubiquitination can regulate both tumor-suppressing and tumor-promoting pathways in cancer. This review outlines how components of the ubiquitination systems (e.g. E3 ligases and deubiquitinases) act as oncogenes or tumor suppressors according to the nature of their substrates. Furthermore, I interrogate how the current knowledge of the differential roles of ubiquitination in cancer lead to technical advances to inhibit or reactivate the components of the ubiquitination system accordingly.

Introduction

Ubiquitination is a posttranslational modification of proteins in both normal homeostasis and disease. This process involves the addition of an evolutionarily conserved small protein, ubiquitin (Ub) or ubiquitin-like proteins (UBLs), to target proteins for proteasome degradation or non-degradative signaling (Hershko, 1983). The Ub signal on modified proteins is covalently coupled to lysine side-chain residues in a sequential manner by a cascade of enzymatic reactions involving collaboration between the activating (E1), conjugating (E2) and ligating (E3) enzymes (Wilkinson, 1987). The C-terminus of Ub is first activated by an E1 enzyme and is then transferred onto the active site cysteine of an E2 conjugating enzyme through trans-thioesterification. Subsequently, E3 Ub ligases (HECT (Homology to E6AP C Terminus) or RING (Really Interesting New Gene)) bind simultaneously the E2-Ub intermediate and the target protein to catalyze isopeptide bond formation between the C-terminal glycine of ubiquitin and the substrate lysine residue (Wang et al., 2017a) (Fig. 1). The human genome contains around 50 genes encoding E2 enzymes and 600 genes encoding E3 ligases. Also, there are more than 90 deubiquitinating enzymes (DUBs), which can remove Ub from the Ub-bound proteins. DUBs can be divided into six classes: ubiquitin C-terminal hydrolases (UCHs), ubiquitin-specific proteases (USPs), ovarian-tumor proteases (OTUs), JAMM/MPN domain-associated metallopeptidases (JAMMs), Machado–Joseph disease protein domain proteases (MJD) and monocyte chemotactic protein-induced protein (MCPIP) (Schulman and Harper, 2009; D’arcy et al., 2015).

The mono-Ub proteins undergo multiple ubiquitination reactions to generate multi mono-Ub proteins or polymeric Ub chains. Both mono-Ub and multi mono-Ub are involved in several biological processes, including endocytosis, DNA repair, and protein localization and trafficking (Popovic et al., 2014). Because ubiquitin itself has seven lysine (K) residues, this modification can be propagated, by transferring additional ubiquitin to one of seven lysine residues or the N-terminus –NH2 group (Ikeda and Dikic, 2008). According to the formed chain topology, ubiquitination can have different biological outcomes. For instance, K48 and K11 chains are related to degradation by the proteasome, whereas K63 and linear ubiquitin chains have a scaffolding role for signaling assemblies and play a prominent role in many biological pathways, including inflammation. However, K6 and K27 poly-ubiquitinated proteins are associated with DNA damage responses and mitochondrial maintenance, respectively. Also, K29 and K33 poly-ubiquitinated proteins are related to lysosomal degradation and T cell receptor (TCR) signaling, respectively (Bennett and Harper, 2008; Pickart and Eddins, 2004; Chen and Sun, 2009) (Fig. 2).

Ubiquitination regulates a variety of complex cellular processes, including protein degradation, protein–protein interactions, endocytosis, cell cycle progression, and activating or inactivating substrates (Pickart and Eddins, 2004). Therefore, any functional mutation or aberrant expression of the Ub system components can lead to several disorders, including cancer, neurodegenerative disorders, and adaptive and innate immunity–related disorders. The physiological functions of ubiquitination are not limited to proteolysis. There are also nonproteolytic roles of ubiquitination such as multi-protein complex assembly, inflammatory signaling, autophagy, DNA repair and regulation of enzymatic activity (Bhattacharjee and Nandi, 2017; Martín-vicente et al., 2017; Kattah et al., 2017).

In cancer, ubiquitination may lead to the activation or deactivation of tumorigenic pathways. Several reports have shown that aberrant expression of E3 ligases and DUBs are associated with human malignancies by regulating the activity or degradation of tumor-promoting or -suppressor proteins. Prominent examples include cyclin-dependent kinase inhibitor 1B (p27), p53 and nuclear factor kappa-B (NF-κB) (Lu and Hunter, 2010; Love et al., 2013; Paul et al., 2017). Unlike kinases, most components of the ubiquitin system do not have well-defined catalytic pockets and require a dynamic rearrangement of multiple protein–protein interactions, making them very difficult for inhibition by small molecules. However, with advances in technologies and better understanding of ubiquitin biology, there have been great developments in the reactivation of the ubiquitination system using cutting-edge methodologies. For instance, protein-targeting chimeric molecules (PROTACs) and hydrophobicity tags (HyT) have been developed to modulate the ubiquitination system and the fate of modified proteins (Huang and Dixit, 2016). In this review, I will discuss how genetic defects in components of the Ub system can mediate progression or suppression of the tumorigenic pathways in different types of cancer. I will also shed light on the current and future perspectives of cancer therapeutics that depend on either activation or deactivation of the ubiquitination of target proteins (Fig. 3).

Section snippets

MDM2/p53 interaction

One of the well-known functions of ubiquitination is the modulation of protein stability through the ubiquitin–proteasome system (UPS) in normal and pathological states. Proteins that are marked by Ub are trafficked to the proteasome or lysosome for degradation (Fig. 1). Mutations or deregulation of the expression of key players in this process, E3 ligases, are found in different carcinomas and usually correlate clinically with poor survival and prognosis (Hoeller and Dikic, 2009; Lipkowitz and

Targeting the proteasome

There are currently two proteasome inhibitors approved by the FDA: bortezomib (Velcade) and carfilzomib (Kyprolis) (Hideshima et al., 2001; Chauhan et al., 2005; Hideshima et al., 2003). As a peptide boronate, bortezomib showed great efficacy in multiple myelomas rather than in solid cancers (Hideshima et al., 2001). Bortezomib stabilizes I-κB, an important suppressor of NF-κB signaling (Chauhan et al., 2005). Also, bortezomib causes accumulation of the tumor suppressors p27KIP1 and p53 (

The von Hippel-Lindau tumor suppressor

The von Hippel-Lindau tumor suppressor (pVHL; encoded by VHL) is named after hereditary cancers characterized by highly vascularized tumors such as renal cell cancer, pancreatic tumors and tumors of the retinal and central nervous system (Gnarra et al., 1994; Kanno et al., 1994). pVHL is a part of the VCB–Cul2–VHL Ub ligase complex, which mediates the ubiquitination of hypoxia-inducible factor-1α (HIF-1α). Once HIF-1α is hydroxylated on proline residues, it undergoes ubiquitination by pVHL and

Targeting tumor-promoting deubiquitinases

As shown previously, several DUBs are deregulated in cancer, leading to abnormal functions of their substrates. Therefore, inhibitors of USPs and other DUBs provide an excellent approach to restore the functions of tumor suppressors (e.g. PTEN and p53) by inducing their stability or modulating their activity in cancer cells. For instance, small molecule inhibitors of USP7 (e.g. HBX41&108) reverse EMT and induce apoptosis in cancer cells (Colland et al., 2009). Importantly, these inhibitors

Conclusions and future perspectives

The process of ubiquitination has a broad spectrum and diverse functions in both normal homeostasis and disease. Aberrant expression and mutations in components of the Ub network have been implicated in several types of cancer. Additionally, cancer cells may take advantage of a combinatorial deregulated expression of these components in order to support oncogenic signaling pathways. The function and ultimate effect of ubiquitination depends mainly on the nature of the effector substrate and

Declarations of interest

None.

Conflict of interest

The author declares no conflict of interest regarding financial and/or personal relationships with other people or organizations that could inappropriately influence (bias) this work.

Acknowledgements

I thank Angela Kelsey, Catherine Winchester and Mark Nakasone at the Beatson Institute for their critical reading and editing of the manuscript. I thank Dr David Bryant at the Institute of Cancer Sciences for his encouragement and useful discussion. I apologize to all researchers whose crucial contributions in the field of ubiquitination were not referenced in this review, due to limitations in space. The author was supported by a Royal Society Newton International Fellowship.

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