The Ubiquitin System: An Emerging Therapeutic Target for Lung Cancer

Abstract

The ubiquitin system, present in all eukaryotes, contributes to regulating multiple types of cellular protein processes such as cell signaling, cell cycle, and receptor trafficking, and it affects the immune response. In most types of cancer, unusual events in ubiquitin-mediated signaling pathway modulation can lead to a variety of clinical outcomes, including tumor formation and metastasis. Similarly, ubiquitination acts as a core component, which contributes to the alteration of cell signaling activity, dictating biosignal turnover and protein fates. As lung cancer acquires the most commonly mutated proteins, changes in the ubiquitination of the proteins contribute to the development of lung cancer. Various inhibitors targeting the ubiquitin system have been developed for clinical applications in lung cancer treatment. In this review, we summarize the current research advances in therapeutics for lung cancer by targeting the ubiquitin system.

Keywords: E3 ligase; cell signaling; deubiquitination; lung cancer; ubiquitin; ubiquitination.

Figure 1

Common risk factors for lung cancer.

Figure 2

The ubiquitination processes. Ubiquitin (Ub) is added to the selected substrates in three phases, each necessitating the use of three enzymes: E1, E2, and E3. Step 1: The ubiquitin-activating enzyme E1 activates ubiquitin in an ATP-dependent manner. Step 2: Ubiquitin is subsequently transported to one of numerous types of E2, the ubiquitin conjugating enzyme. Step 3: The attachment of ubiquitin to the protein substrate is mediated by one of many E3s. The 26S proteasome recognizes polyubiquinated proteins and degrades them. Small peptides and reusable free ubiquitin are produced by their cleavage. Deubiquitination catalyzes the removal of Ub from substrate proteins.