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COMMD1 disrupts HIF-1α/β dimerization and inhibits human tumor cell invasion
Bart van de Sluis, … , Marc Vooijs, Ezra Burstein
Bart van de Sluis, … , Marc Vooijs, Ezra Burstein
Published May 10, 2010
Citation Information: J Clin Invest. 2010;120(6):2119-2130. https://doi.org/10.1172/JCI40583.
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Research Article Oncology Article has an altmetric score of 3

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

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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.

Authors

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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Figure 2

COMMD1 repression promotes tumor invasion.

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COMMD1 repression promotes tumor invasion.
(A–C) HT29 or U2OS cells were...
(A–C) HT29 or U2OS cells were infected with lentiviruses expressing short hairpin sequences targeting COMMD1 (shCOMMD1) or a control gene (shControl). (A) Western blot analysis demonstrating the decrease in COMMD1 levels in the cell lines used is shown. These cells were tested for invasion of the chick CAM, as described in the Methods section. (B) Representative images of H&E and immunofluorescence staining (IF) are shown (laminin, red; DAPI, blue; cancer cells, green). Cell invasion into the CAM is indicated with white arrows (original magnification, ×200 [HT29]; ×100 [U2OS]). (C–E) B16.F10 mouse melanoma cells were stably transfected to express COMMD1-FLAG (as shown in the Western blot in C). These cells were subsequently injected into the tail vein of syngeneic C57BL6 mice (2 × 105 cells/mouse), and (D) after 15 days, the mice were sacrificed, and the number of lung metastasis per mouse was counted (the horizontal bars represent the mean in each group). The Student’s t test was used for statistical analysis. (E) Representative images of the lungs of these mice are shown.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 2 patents
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