Neddylation: a novel modulator of the tumor microenvironment

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.

SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors -1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets

“…In particular, the emerging evidence related to the biological activity of SerpinB3 in tumor microenvironment is of relevance since it outlines two putative novel therapeutic targets involved in cell proliferation and HCC development and progression. Neddylation, a post-translational modification that adds an ubiquitin-like protein NEDD8 to substrate proteins, then affecting their stability as well as their subcellular localization, conformation, and function, has been reported to be over-activated in different human cancers, including lung cancer, intrahepatic cholangiocarcinoma, HCC, colorectal cancer, glioblastoma, nasopharyngeal carcinoma, and esophageal squamous cell carcinoma [31,42,57,58]. Accordingly, targeting the NEDDylation pathway is representing a potential and attractive anticancer therapeutic strategy.…”

“…Accordingly, targeting the NEDDylation pathway is representing a potential and attractive anticancer therapeutic strategy. Of relevance, the NEDD8-activating enzyme (NAE) inhibitor MLN4924 has been demonstrated to exhibit potent antitumor activity and to be well-tolerated in preclinical studies [34,42,59]. Actually, MLN4924 entered into phase I/II/III clinical trials for patients suffering from solid tumors other than HCC as well as hematologic malignancies [42].…”

“…Of relevance, the NEDD8-activating enzyme (NAE) inhibitor MLN4924 has been demonstrated to exhibit potent antitumor activity and to be well-tolerated in preclinical studies [34,42,59]. Actually, MLN4924 entered into phase I/II/III clinical trials for patients suffering from solid tumors other than HCC as well as hematologic malignancies [42]. In particular, 33 clinical trials have been enrolled in clinicaltrials.gov website (https://www.clinicaltrials.gov/), and eight completed phase I clinical trials demonstrated that MLN4924 is safe and feasible.…”

“…Accordingly, we next considered other post-translational modifications of cellular proteins, by focusing our attention to the involvement of NEDD8 and NEDDylation process in the stabilization of proteins with essential regulatory roles [30]. Concerning NEDD8-related target proteins, the substrates were divided into cullins and non-cullins, including p53, MDM2, pVHL, HIF-1α/HIF-2α, HuR, and more [42,43]. Cullins are a major family of proteins that are subunits of the E3 ligase machinery, which brings together E2 ubiquitin-conjugating enzymes and substrates that have been targeted for degradation.…”

Ubiquitin and Ubiquitin-Like Proteins Are Essential Regulators of DNA Damage Bypass

“…Aside from the up/down regulation or mutation of individual TLS polymerases, deregulation of DNA damage bypass by ubiquitin and ubiquitin-like proteins may also play a significant role in driving carcinogenesis. This includes the altered expression of ubiquitin and ubiquitin-like proteins themselves; NEDD8 and ISG15, for example, are overexpressed in many cancers [ 87 , 88 , 89 ]. In addition, numerous ubiquitin and ubiquitin-like metabolism proteins directly associated with DNA damage bypass are deregulated in various cancers ( Table 1 ).…”