COMMD1 disrupts HIF-1α/β dimerization and inhibits human tumor cell invasion

Abstract

The gene encoding COMM domain-containing 1 (COMMD1) is a prototypical member of the COMMD gene family that has been shown to inhibit both NF-κB-and HIF-mediated gene expression. NF-κB and HIF are transcription factors that have been shown to play a role in promoting tumor growth, survival, and invasion. In this study, we demonstrate that COMMD1 expression is frequently suppressed in human cancer and that decreased COMMD1 expression correlates with a more invasive tumor phenotype. We found that direct repression of COMMD1 in human cell lines led to increased tumor invasion in a chick xenograft model, while increased COMMD1 expression in mouse melanoma cells led to decreased lung metastasis in a mouse model. Decreased COMMD1 expression also correlated with increased expression of genes known to promote cancer cell invasiveness, including direct targets of HIF. Mechanistically, our studies show that COMMD1 inhibits HIF-mediated gene expression by binding directly to the amino terminus of HIF-1α, preventing its dimerization with HIF-1β and subsequent DNA binding and transcriptional activation. Altogether, our findings demonstrate a role for COMMD1 in tumor invasion and provide a detailed mechanism of how this factor regulates the HIF pathway in cancer cells.

Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems

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Steroid Receptor Coactivator-3 Regulates Glucose Metabolism in Bladder Cancer Cells through Coactivation of Hypoxia Inducible Factor 1α

“…Immunoprecipitation, GST Pull-down, and Western Blotting Assays-Immunoprecipitation assay was described previously (23). Briefly, transfected cells were lysed in lysis buffer (20 mM Tris-HCl, pH 8.0, 125 mM NaCl, 0.5% Nonidet P-40, 2 mM EDTA, 0.2 mM NaF, 0.2 mM Na 3 VO 4 , protease inhibitor mixture) for 30 min, followed by centrifugation at 12,000 ϫ g for 20 min at 4°C to remove debris.…”

p16 Protein and Gigaxonin Are Associated with the Ubiquitination of NFκB in Cisplatin-induced Senescence of Cancer Cells

“…NFB is involved in cellular responses to stressful stimuli such as cytokines, UV irradiation, free radicals (including cigarette smoke), hypoxia, and infectious agents (11,12). Activation of NFB is increased in many cancers and is associated with various steps in the development of malignancy such as expression of anti-apoptotic genes, angiogenesis, tumor promotion, and metastasis (9).…”