The NEDD8-activating enzyme E1 UBA3 orchestrates the immunosuppressive microenvironment in lung adenocarcinoma via the NF-кB pathway.

Immunosuppressive cells play important roles in generating an immunosuppressive tumor microenvironment and facilitating tumor immune escape. However, the molecular mechanisms underlying their immunosuppressive effects remain unclear. UBA3, the sole catalytic subunit of the neural precursor cell expressed developmentally down-regulated protein 8 (NEDD8)-activating enzyme E1, is highly expressed in various human malignancies, along with an activated neddylation pathway. In this study, we investigated the relationships between the UBA3-dependent neddylation pathway and the infiltration of several immunosuppressive cell populations in lung adenocarcinoma (LUAD). We explored the regulatory mechanisms of UBA3 in LUAD cells by using mRNA sequencing and functional enrichment analyses. Correlations between neddylation and immune infiltrates were assessed by Western blotting, real-time PCR, and analyses of public databases. We found elevated levels of UBA3 expression in LUAD tissues compared to adjacent normal tissues. Blocking UBA3 and the neddylation pathway promoted the accumulation of the phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (p-IκBα), inhibiting the gene expression of tumor cell-derived cytokines such as C-C motif chemokine ligand (CCL) 2, C-X-C motif ligand (CXCL)1, CXCL2, colony-stimulating factor (CSF) 1, CSF2 interleukin (IL)-6, and IL-1B. Moreover, the overexpression of UBA3 in LUAD cells was associated with the secretion of these cytokines, and the recruitment and infiltration of immunosuppressive cells including tumor-associated macrophages (TAMs), plasmacytoid dendritic cells (pDCs), Th2 cells and T-regulatory cells (Tregs). This could facilitate the tumor immune escape and malignant progression of LUAD. Our findings provide new insights into the role of UBA3 in establishing an immunosuppressive tumor microenvironment by modulating nuclear factor kappa B (NF-кB) signaling and the neddylation pathway.

NEDD8-conjugating enzyme E2s: critical targets for cancer therapy.

NEDD8-conjugating enzymes, E2s, include the well-studied ubiquitin-conjugating enzyme E2 M (UBE2M) and the poorly characterized ubiquitin-conjugating enzyme E2 F (UBE2F). UBE2M and UBE2F have distinct and prominent roles in catalyzing the neddylation of Cullin or non-Cullin substrates. These enzymes are overexpressed in various malignancies, conferring a worse overall survival. Targeting UBE2M to influence tumor growth by either modulating several biological responses of tumor cells (such as DNA-damage response, apoptosis, or senescence) or regulating the anti-tumor immunity holds strong therapeutic potential. Multiple inhibitors that target the interaction between UBE2M and defective cullin neddylation protein 1 (DCN1), a co-E3 for neddylation, exhibit promising anti-tumor effects. By contrast, the potential benefits of targeting UBE2F are still to be explored. It is currently reported to inhibit apoptosis and then induce cell growth; hence, targeting UBE2F serves as an effective chemo-/radiosensitizing strategy by triggering apoptosis. This review highlights the most recent advances in the roles of UBE2M and UBE2F in tumor progression, indicating these E2s as two promising anti-tumor targets.

Neddylation pathway promotes myeloid-derived suppressor cell infiltration via NF-κB-mCXCL5 signaling in lung cancer.

Myeloid-derived suppressor cells (MDSCs), a population derived from immature myeloid progenitors, are present in the tumors of patients and highly protumorigenic. However, the molecular mechanisms regulating MDSC infiltration remain unclear. Neddylation pathway is overactivated in multiple cancers and has a significant role in tumor progression. We established a subcutaneous transplantation model of Lewis lung cancer in mice and showed that inactivation of neddylation pathway inhibits MDSC infiltration and impairs lung cancer growth. A high expression level of neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8) is positively correlated with MDSC infiltration in human lung adenocarcinomas (LUADs). Moreover, inactivation of neddylation pathway inhibits the expression of murine CXCL5 (mCXCL5; human homolog CXCL6, hCXCL6), an important cytokine implicated in MDSC recruitment. Mechanistically, inactivation of neddylation pathway inhibits activity of Cullin-RING ligase 1, a typical neddylation substrate, and induces accumulation of phosphorylated IκBα and subsequent blockage of NF-κB translocation, thus suppressing transcriptional activation of mCxcl5 or hCXCL6. Collectively, our data suggest that neddylation-NF-κB-mCXCL5 axis is involved in MDSC recruitment to the tumor sites and demonstrate that neddylation pathway is a good therapeutic target for patients with LUAD, particularly those receiving anti-MDSC therapy.