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Elevated Neddylation Pathway Promotes Th2 Cells Infiltration by Transactivating STAT5A in Hepatocellular Carcinoma.

ABSTRACT: Neddylation is a process in which a ubiquitin-like molecule NEDD8 is conjugated to a lysine residue of the substrate protein via successive enzymatic cascade reactions. Inactivation of neddylation pathway triggers tumor cell apoptosis or senescence to suppress the tumor growth. So far, there has been limited research on the role of the neddylation pathway (NEDD8-UBE2M-RBX1 axis) in the immune response. In this study, we investigated the association between the neddylation pathway and immune function in HCC by comprehensively analyzing transcriptome and clinical data of HCC samples from TCGA database. The analysis showed that the mRNA expression of neddylation pathway components was up-regulated in HCC and increased with disease severity. Moreover, we observed that activated neddylation pathway was associated with enriched infiltration of T helper 2 (Th2) cells in HCC, while transactivation of STAT5A signaling may mediate this association. On the contrary, no significant correlation between the neddylation pathway and Th1 cells infiltration was identified. Taken together, these findings suggest a potential role of the neddylation pathway in promoting a shift in Th1/Th2 balance toward Th2-dominant immunosuppression. Hence, targeting neddylation pathway could serve as an attractive immunotherapy strategy for suppressing the development of Th2 cells.

SUBMITTER: Zhou L

PROVIDER: S-EPMC8602568 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundOur previous studies have shown that regulatory factor X5 (RFX5), a classical transcription regulator of MHCII genes, was obviously overexpressed in hepatocellular carcinoma (HCC) tumors. However, the role of RFX5 in the carcinogenesis and progress of HCC remains unknown. This study aimed to reveal its biological significance and the underlying mechanism in HCC.MethodsRFX5 mRNA expression level and copy number variation in HCC tumors and cell lines were determined by analyzing deposited data sets in the Cancer Genome Atlas and Gene Expression Omnibus database. The biological significance of RFX5 in HCC was investigated by monitoring the colony formation and subcutaneous tumor growth capacity when RFX5 was silenced with lentiviral short hairpin RNA and CRISPR/Cas9 system in HCC cell lines. The downstream gene transcriptionally activated by RFX5 in HCC cells was determined by chromatin immunoprecipitation and luciferase reporter assay. The involvement of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta (YWHAQ) in HCC development was further determined by performing colony formation rescue assay and subcutaneous tumor growth rescue experiment. The association of YWHAQ with recurrence-free survival of patients with HCC was assessed by Kaplan-Meier analysis. Moreover, apoptosis level and the protein level of p53 pathway were determined to reveal the mechanism of RFX5 in driving HCC development.ResultsRFX5 was amplified and highly overexpressed in HCC tumor tissues compared with the corresponding non-tumor tissues. The mRNA expression level of RFX5 was significantly correlated with its DNA copy number (r = 0.4, P < 0.001). Functional study demonstrated that RFX5 was required for both clonogenic forming in vitro and subcutaneous tumor growth in vivo of HCC cells. Further study identified YWHAQ, namely 14-3-3 tau, as a key downstream transcriptional target gene of RFX5, which was tightly regulated by RFX5 in HCC. Moreover, overexpression of YWHAQ largely rescued the clonogenic growth of HCC cells that was suppressed by RFX5 knockdown. In addition, overexpression of YWHAQ in primary tumor was linked to poor prognosis of patients with HCC. These results demonstrated that YWHAQ was a downstream effector of RFX5 in HCC. Notably, RFX5-YWHAQ pathway could protect cells from apoptosis by suppressing the p53 and Bax in HCC.ConclusionRFX5 is a putative HCC driver gene that plays an important role in the development and progression of HCC by transactivating YWHAQ and suppressing apoptosis.

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Elevated Neddylation Pathway Promotes Th2 Cells Infiltration by Transactivating STAT5A in Hepatocellular Carcinoma.

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