Role of E3 ubiquitin ligases in lung cancer

Abstract

E3 ubiquitin ligases are a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome. Therefore, E3 ubiquitin ligases play an essential role in a variety of biological processes including cell cycle regulation, proliferation and apoptosis. E3 ubiquitin ligases are often found overexpressed in human cancers, including lung cancer, and their deregulation has been shown to contribute to cancer development. However, the lack of specific inhibitors in clinical trials is a major issue in targeting E3 ubiquitin ligases with currently only one E3 ubiquitin ligase inhibitor being tested in the clinical setting. In this review, we focus on E3 ubiquitin ligases that have been found deregulated in lung cancer. Furthermore, we discuss the processes in which they are involved and evaluate them as potential anti-cancer targets. By better understanding the mechanisms by which E3 ubiquitin ligases regulate biological processes and their exact role in carcinogenesis, we can improve the development of specific E3 ubiquitin ligase inhibitors and pave the way for novel treatment strategies for cancer patients.

Keywords: Apoptosis; Bortezomib; DNA repair; E3 ubiquitin ligases; Gene regulation; Lung cancer; Proteasome inhibitors; Ubiquitin-proteasome system.

Figure 1

Ubiquitin molecules are covalently conjugated to targeted proteins in a three-step enzymatic cascade. First, an E1 ubiquitin-activating enzyme activates ubiquitin in an adenosine triphosphate (ATP)-dependent manner. Activated ubiquitin is then transferred to the E1 enzyme, followed by the transfer of ubiquitin to an E2 ubiquitin-conjugating enzyme. Finally, an E3 ubiquitin protein ligase recognizes the target proteins and mediates the conjugation of one or more ubiquitin molecules to a lysine residue on the targeted proteins. Really interesting new gene (RING) E3 ubiquitin ligases mediate the direct transfer of ubiquitin from E2 to the targeted substrate whereas Homologous to the E6-associated protein (E6-AP) carboxyl terminus (HECT) E3 ubiquitin ligases first interact with the cognate E2, followed by linkage with ubiquitin and subsequent transfer of ubiquitin to the targeted substrate. AMP: Adenosine monophosphate.