Background: Lung cancer has emerged as one of the most common cancers in recent years. The mitochondrial electron transport chain (ETC) is closely connected with metabolic pathways and inflammatory response. However, the influence of ETC-associated genes on the tumor immune response and the pathogenesis of lung cancer is not clear and needs further exploration.Methods: The RNA-sequencing transcriptome and clinical characteristic data of LUAD were downloaded from the Cancer Genome Atlas (TCGA) database. The LASSO algorithm was used to build the risk signature, and the prediction model was evaluated by the survival analysis and receiver operating characteristic curve. We explored the function of FDX1 through flow cytometry, molecular biological methods, and liquid chromatography–tandem mass spectrometry/mass spectrometry (LC–MS/MS).Results: 12 genes (FDX1, FDX2, LOXL2, ASPH, GLRX2, ALDH2, CYCS, AKR1A1, MAOB, RDH16, CYBB, and CYB5A) were selected to build the risk signature, and the risk score was calculated with the coefficients from the LASSO algorithm. The 1-year, 3-year, and 5-year area under the curve (AUC) of ROC curves of the dataset were 0.7, 0.674, and 0.692, respectively. Univariate Cox analysis and multivariate Cox regression analysis indicated that the risk signature is an independent risk factor for LUAD patients. Among these genes, we focused on the FDX1 gene, and we found that knockdown of FDX1 neither inhibited tumor cell growth nor did it induce apoptosis or abnormal cell cycle distribution. But FDX1 could promote the ATP production. Furthermore, our study showed that FDX1 was closely related to the glucose metabolism, fatty acid oxidation, and amino acid metabolism.Conclusion: Collectively, this study provides new clues about carcinogenesis induced by ETC-associated genes in LUAD and paves the way for finding potential targets of LUAD.

Hepatitis B virus (HBV) infection is one of main contributors to poor prognosis and rapid progression of hepatocellular cancer (HCC). We previously identified the important role of the phosphorylation of ubiquitin-like with PHD and ring finger domains (UHRF2) in HBV-associated HCC. In this study we identify upregulated UHRF2 protein levels in HBV-associated HCC cells and tissues. UHRF2 overexpression promotes the viability, proliferation, migration and invasiveness of HBV-positive HCC cell lines, and enhances HBV DNA replication. To obtain a comprehensive understanding of the interaction networks of UHRF2 and their underlying mechanism, this study suggests that UHRF2 facilitates the ubiquitin-proteasome-mediated proteolysis of DExD/H (Asp-Glu-Ala-His) -box helicase enzyme 9 (DHX9). However, phosphorylation of UHRF2 by HBx at S643 inhibits E3 ubiquitin ligase activity of UHRF2 and improves DHX9 protein stability. Furthermore, results suggest that HBx promotes phosphorylation of UHRF2 by the ETS1-CDK2 axis through the downregulation of miR-222-3p in HBV-associated HCC specimens and cells. Our findings suggest that HBx-induced phosphorylation of UHRF2 S643 acts as a “switch” in HBV-associated HCC oncogenesis, activating the positive feedback between phosphorylated UHRF2 and HBV, provide evidence that UHRF2 is a new regulator and a potential prognostic indicator of poor prognosis for HBV-associated HCC.

Autophagy have critical implications in the proliferation and metastasis of HCC. In the current study, we aimed to explore the underlying mechanisms of UHRF2 regulates HCC cells autophagy and HCC progression. We initially determined the relationship between UHRF2 and HCC autophagy, oncogenicity and patient survival through GSEA database and TCGA database. We mainly investigated the effect of UHRF2 on HCC development and autophagy through western blot, electron microscopy, and immunofluorescence. Functionally, UHRF2 was positively involved in the autophagy activation. Overexpression of UHRF2 reduced apoptosis in HCC cells, and promoted the malignancy phenotype of HCC both in vitro and in vivo. Mechanistically, PRDX1 bound to UHRF2 and upregulated its protein expression to facilitate the biological function of UHRF2 in HCC. Meanwhile, UHRF2 bound to autophagy-related protein PARP1 and upregulated PARP1 protein level. The results showed that UHRF2 promoted autophagy and contributed to the malignant phenotype of HCC by regulating PARP1 protein level. In summary, a novel interaction between PRDX1, UHRF2, and PARP1 was revealed, suggesting that UHRF2 could inspire a potential biomarker and potential therapeutic target for HCC.

Ubiquitin-like with PHD and ring finger domains 2 (UHRF2) is a multi-domain E3 ubiquitin ligase which is involved in epigenetic regulation and plays an essential role in tumorigenesis. However, the role of UHRF2 in histone H3 acetylation has not yet been fully elucidated and few studies have reported its role in hepatocellular carcinoma (HCC). In this study, we examined the correlation between UHRF2 and acetylated H3 in HCC. Immunohistochemistry and western blot analysis demonstrated that the levels of histone H3 lysine 9 acetylation (H3K9ac) and histone H3 lysine 14 acetylation (H3K14ac) were higher in the HCC tissues and HepG2 HCC cells compared with the adjacent non-tumor tissues and L02 normal cells. The level of UHRF2 was higher in the HCC tissues compared with the adjacent non-tumor tissues, but its expression did not exhibit a significant difference between the HepG2 HCC cells and the L02 normal cells. In addition, when comparing the HCC tissues, a higher expression of UHRF2 correlated with a lower expression of H3K9ac in the HCC tissues. The overexpression of UHRF2 increased the expression of H3K9ac in L02 normal cells (P<0.01), but decreased the expression of H3K9ac in HepG2 cancer cells (P<0.05). Moreover, immunofluorescence staining and co-immunoprecipitation assay indicated that UHRF2 co-localized and interacted with H3K9ac in L02 and HepG2 cells and the plant homeodomain (PHD) finger domain was the key domain for UHRF2 directly binding to H3K9ac. Taken together, these results suggest that UHRF2 decreases the expression of H3K9ac in HepG2 HCC cells and interacts with it through the PHD domain.

Emerging evidence revealed that UHRF2 was implicated in a variety of human diseases, especially in cancer. However, the biological function, clinical significance and underly mechanisms of UHRF2 in hepatocellular carcinoma (HCC) is largely unknown. We analyzed the expression of UHRF2 in 371 HCC tissues and 50 para-cancerous tissues of TCGA database. We found that UHRF2 was significantly upregulated in HCC tissues, which was further confirmed in HCC cells and tissues by western blot. More importantly, the level of UHRF2 was correlated with pathological grade and clinical stage, and the patients with high level of UHRF2 had lower overall survival, disease-free survival and higher recurrence rate than those with low UHRF2 level. Univariate and multivariate Cox regression analysis revealed that high level of UHRF2 might be an independent prognostic factor for HCC patients. Functional investigations suggested that ectopic expression of UHRF2 could promote the proliferation, migration and invasion of HCC cell lines, whereas knock down of UHRF2 exhibited an opposite effect. Additionally, gene set enrichment analysis indicated that ERBB signaling pathway was upregulated in patients with high level of UHRF2. Pearson correlation analysis indicated that the expression of UHRF2 was positively correlated with ErbB3 and its downstream targets SOS1, Ras and Raf-1. Furthermore, we found that overexpression of UHRF2 could upregulate the expression of ErbB3, SOS1, Ras and Raf-1. Our findings suggested that UHRF2 might accelerate HCC progression by upregulating ErbB3/Ras/Raf signaling pathway and it might serve as a diagnostic marker and therapeutic target for HCC patients.