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- Title
COMMD1 disrupts HIF-1alpha/beta dimerization and inhibits human tumor cell invasion.
- Authors
van de Sluis, Bart; Xicheng Mao; Yali Zhai; Groot, Arjan J.; Vermeulen, Jeroen F.; van der Wall, Elsken; van Diest, Paul J.; Hofker, Marten H.; Wijmenga, Cisca; Klomp, Leo W.; Cho, Kathleen R.; Fearon, Eric R.; Vooijs, Marc; Burstein, Ezra; Mao, Xicheng; Zhai, Yali
- 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-kappaB- and HIF-mediated gene expression. NF-kappaB 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-1alpha, preventing its dimerization with HIF-1beta 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.
- Subjects
GENE expression; MELANOMA; GENETIC transcription; XENOGRAFTS; CANCER cells; METASTASIS; DNA-ligand interactions; PROTEIN metabolism; ANIMAL experimentation; BIOCHEMISTRY; CARRIER proteins; CELL lines; COMPARATIVE studies; LUNG tumors; PHENOMENOLOGY; RESEARCH methodology; MEDICAL cooperation; MICE; PROTEINS; RESEARCH; TRANSCRIPTION factors; TUMORS; DNA-binding proteins; EVALUATION research; DIMERIZATION
- Publication
Journal of Clinical Investigation, 2010, Vol 120, Issue 6, p2119
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI40583