Abstract
Neddylation, a post-translational modification that adds an ubiquitin-like protein NEDD8 to substrate proteins, modulates many important biological processes, including tumorigenesis. The process of protein neddylation is overactivated in multiple human cancers, providing a sound rationale for its targeting as an attractive anticancer therapeutic strategy, as evidence by the development of NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Neddylation inhibition by MLN4924 exerts significantly anticancer effects mainly by triggering cell apoptosis, senescence and autophagy. Recently, intensive evidences reveal that inhibition of neddylation pathway, in addition to acting on tumor cells, also influences the functions of multiple important components of the tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts (CAFs), cancer-associated endothelial cells (CAEs) and some factors, all of which are crucial for tumorigenesis. Here, we briefly summarize the latest progresses in this field to clarify the roles of neddylation in the TME, thus highlighting the overall anticancer efficacy of neddylaton inhibition.
Highlights
Neddylation is a reversible covalent conjugation of an ubiquitin-like molecule Neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to a lysine residue of the substrate protein [1, 2]
Intensive studies have proven that NEDD8 and enzymes of neddylation pathway (e.g. NEDD8 activating enzyme E1 subunit 1 (NAE1)/Ubiquitin like modifier activating enzyme 3 (UBA3), Ubiquitin conjugating enzyme E2 M (UBE2M)/ Ubiquitin conjugating enzyme E2 F (UBE2F) and NEDD8 E3 ligases) are often overexpressed in multiple human cancers, which is associated with disease progression and predicts poor patient survival [20–27]
Recent and ongoing investigations highlight a pivotal role of neddylation pathway in tumor biology and immune cell development
Summary
Neddylation is a reversible covalent conjugation of an ubiquitin-like molecule NEDD8 (neuronal precursor cell-expressed developmentally down-regulated protein 8) to a lysine residue of the substrate protein [1, 2]. MLN4924 effectively blocks cullin neddylation and inactivates CRLs, leading to accumulation of various CRLs substrates, triggering multiple cellular responses, including cell cycle arrest, apoptosis, senescence and autophagy in a cell-type dependent manner [12, 28–31]. We first determined the differentially expressed genes associated with neddylation inhibition by MLN4924 in lung cancer cells in vitro.
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