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Review
. 2019 Apr 3;18(1):77.
doi: 10.1186/s12943-019-0979-1.

Neddylation: a novel modulator of the tumor microenvironment

Lisha Zhou  1   2 , Yanyu Jiang  3 , Qin Luo  4 , Lihui Li  4 , Lijun Jia  5
Affiliations
Review

Neddylation: a novel modulator of the tumor microenvironment

Lisha Zhou et al. Mol Cancer. .

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.

Keywords: Cancer-associated endothelial cells; Cancer-associated fibroblasts; Immune cells; Neddylation; Tumor microenvironment; Tumor-derived factors.

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Figures

Fig. 1
Fig. 1
The process of protein modification by neddylation. Neddylation is a process of conjugating NEDD8, an ubiquitin-like molecule, to targeted protein substrates via enzymatic cascades involving NEDD8-activating enzyme E1, NEDD8-conjuagating enzyme E2 and substrate-specific NEDD8-E3 ligases. Shown are reported neddylation E1/E2s/E3s and substrates. The substrates were divided into cullins and non-cullins. N8: NEDD8
Fig. 2
Fig. 2
Neddylation acts as a modulator of tumor-derived factors. a KEGG pathway enrichment analysis of down-regulated genes induced by MLN4924 in lung cancer cells. b Most of the 22 MDSCs-related genes were down-regulated with MLN4924 treatment. H1299 lung cancer cells treated with 1 μM MLN4924 for 12 h, were used for gene expression profiling
Fig. 3
Fig. 3
Neddylation acts as a modulator of cancer-associated fibroblasts (CAFs). a KEGG pathway enrichment analysis of down-regulated genes induced by MLN4924 in CAFs. CAFs were isolated from hepatocellular carcinoma (HCC) tissues, and treated with 1 μM MLN4924 for 12 h. b The expression of several inflammatory cytokines was reduced upon MLN4924 treatment. c-d Neddylation inhibition, either by MLN4924 treatment or siRNA-mediated depletion of NEDD8 or NAE1, suppressed CAFs migration. Conditioned medium (CM) collected from supernatants of HCC cells was used for chemotaxis assay. 5 × 104 isolated CAFs were placed into the upper chamber and treated with MLN4924 for 12 h at 37 °C. Cells that migrated were fixed and stained, followed by counting the cell number under a Leica microscope to measure. NC: Negative control. Scale bar for× 200 images, 50 μm
Fig. 4
Fig. 4
Inhibition of neddylation pathway impairs migration, proliferation and survival of endothelial cells by accumulation of CRL substrates
Fig. 5
Fig. 5
Neddylation pathway plays a crucial role in the modulation of TME. 1) Neddylation inhibition suppresses the activation of tumor-associated fibroblasts (CAFs) and tumor-associated endothelial cells (CAEs). 2) Neddylation inhibition suppresses immune cells, including T cells, dendritic cells and macrophages
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