title: COMMD1 disrupts HIF-1alpha/beta 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-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.
authors.affiliation: Complex Genetics Section, Division of Biomedical Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van de Sluis
authors.forename: Xicheng
authors.initials: X
authors.lastname: Mao
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhai
authors.forename: Arjan J
authors.initials: AJ
authors.lastname: Groot
authors.forename: Jeroen F
authors.initials: JF
authors.lastname: Vermeulen
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Leo W
authors.initials: LW
authors.lastname: Klomp
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Cho
authors.forename: Eric R
authors.initials: ER
authors.lastname: Fearon
authors.forename: Marc
authors.initials: M
authors.lastname: Vooijs
authors.forename: Ezra
authors.initials: E
authors.lastname: Burstein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics; D055503:Protein Multimerization; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C480519:COMMD1 protein, human; D002352:Carrier Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014157:Transcription Factors
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