An NF-κB/OVOL2 circuit regulates glucose import and cell survival in non-small cell lung cancer

Abstract

Background Tumor cells tend to utilize glycolysis rather than aerobic respiration even under aerobic conditions. OVOL2, an inhibitory C2H2 zinc finger transcription factor, is a potential tumor suppressor in cancers. However, the association between OVOL2 and tumor energy metabolism is unknown. Methods Western blotting was used to determine the expression of OVOL2 in different non-small cell lung cancer (NSCLC) cell lines and mouse models. The metabolic parameters in NSCLC cells following overexpression or knockdown OVOL2 were examined. To define the mechanism by which OVOL2 regulates aerobic glycolysis, interacting protein of OVOl2 and downstream molecular events were identified by luciferase assay and co-immunoprecipitation. We documented the regulatory mechanism in mouse xenograft models. Finally, clinical relevance of OVOL2, NF-κB signaling and GLUT1 was measured by immunostaining. Results OVOL2 is downregulated in NSCLC and overexpression of OVOL2 inhibits the survival of cancer cells. Moreover, OVOL2 directly binds to P65 and inhibits the recruitment of P300 but facilitates the binding of HDAC1 to P65, which in turn negatively regulates NF-κB signaling to suppress GLUT1 translocation and glucose import. In contrast, OVOL2 expression is negatively regulated by NF-κB signaling in NSCLC cells via the ubiquitin–proteasome pathway. Re-expression of OVOL2 significantly compromise NF-κB signaling-induced GLUT1 translocation, aerobic glycolysis in NSCLC cells and mouse models. Immunostaining revealed inverse correlations between the OVOL2 and phosphorylated P65 levels and between the OVOL2 and membrane GLUT1 levels, and a strong correlation between the phosphorylated P65 and membrane GLUT1 levels. Conclusions These results suggest a regulatory circuit linking NF-κB and OVOL2, which highlights the role of NF-κB signaling and OVOL2 in the modulation of glucose metabolism in NSCLC.

OVOL2 induces autophagy-mediated epithelial-mesenchymal transition by the ERK1/2 MAPK signaling in lung adenocarcinoma

“…Previous studies have confirmed that OVOL2 plays an important role in tumor development and metastasis. 20 , 21 , 22 In our study, we first found that the expression level of OVOL2 was significantly reduced in LUAD tumor tissues and negatively correlated with the OS and DFS of patients with LUAD using a large-scale LUAD tissue microarray. Low OVOL2 expression was an independent risk factor in patients with LUAD that had poor prognosis and was significantly associated with clinicopathological features, such as tumor size, LN metastasis, and TNM stage.…”

Gene Expression Responses in Bronchial Epithelial Cells Exposed to Vanadium

“…NF-κB signaling could negatively regulate the expression of OVOL2 which was downregulated in NSCLC cells. In addition, OVOL2 overexpression signi cantly compromise the GLUT1 translocation and aerobic glycolysis induced by NF-κB signaling in NSCLC cells [33]. Inhibition of NF-κB and TGF-beta/pSmad2 pathways could effectively relieve the injury and restrain the in ammation in the irradiated lung [34].…”

A Meta-Analysis Approach to Gene Regulatory Network Inference Identifies Key Regulators of Cardiovascular Diseases

“…Furthermore, these genes display enrichment in their regulatory regions for a motif recognized by the transcription factor OVOL2 (Supplementary S1) that is known to be involved in angiogenesis and heart formation [39]. Although there is no data supporting its association with cardiac pathologies, OVOL2 has recently been associated with corneal dystrophy and various types of tumors, such as lung cancer and thyroid cancer [40][41][42]. To the best of our knowledge, its role in cardiac disorders has not been previously reported [39].…”