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

Bart Van De Sluis, Xicheng Mao, Yali Zhai, Arjan J. Groot, Jeroen F. Vermeulen, Elsken Van Der Wall, Paul J. Van Diest, Marten H. Hofker, Cisca Wijmenga, Leo W. Klomp, Kathleen R. Cho, Eric R. Fearon, Marc Vooijs, Ezra Burstein

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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.

Original languageEnglish (US)
Pages (from-to)2119-2130
Number of pages12
JournalJournal of Clinical Investigation
Volume120
Issue number6
DOIs
StatePublished - Jun 1 2010

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Dimerization
Neoplasms
Gene Expression
Heterografts
Transcriptional Activation
Genes
Melanoma
Transcription Factors
Neoplasm Metastasis
Phenotype
Cell Line
Lung
Survival
DNA
Growth

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Van De Sluis, B., Mao, X., Zhai, Y., Groot, A. J., Vermeulen, J. F., Van Der Wall, E., ... Burstein, E. (2010). COMMD1 disrupts HIF-1α/β dimerization and inhibits human tumor cell invasion. Journal of Clinical Investigation, 120(6), 2119-2130. https://doi.org/10.1172/JCI40583

COMMD1 disrupts HIF-1α/β dimerization and inhibits human tumor cell invasion. / Van De Sluis, Bart; Mao, Xicheng; Zhai, Yali; 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.

In: Journal of Clinical Investigation, Vol. 120, No. 6, 01.06.2010, p. 2119-2130.

Research output: Contribution to journalArticle

Van De Sluis, B, Mao, X, Zhai, Y, Groot, AJ, Vermeulen, JF, Van Der Wall, E, Van Diest, PJ, Hofker, MH, Wijmenga, C, Klomp, LW, Cho, KR, Fearon, ER, Vooijs, M & Burstein, E 2010, 'COMMD1 disrupts HIF-1α/β dimerization and inhibits human tumor cell invasion', Journal of Clinical Investigation, vol. 120, no. 6, pp. 2119-2130. https://doi.org/10.1172/JCI40583
Van De Sluis B, Mao X, Zhai Y, Groot AJ, Vermeulen JF, Van Der Wall E et al. COMMD1 disrupts HIF-1α/β dimerization and inhibits human tumor cell invasion. Journal of Clinical Investigation. 2010 Jun 1;120(6):2119-2130. https://doi.org/10.1172/JCI40583
Van De Sluis, Bart ; Mao, Xicheng ; Zhai, Yali ; 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. / COMMD1 disrupts HIF-1α/β dimerization and inhibits human tumor cell invasion. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 6. pp. 2119-2130.
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