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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

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 1

Decreased COMMD1 expression is found in several cancers.

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Decreased COMMD1 expression is found in several cancers.
   
(A and B) C...
(A and B) COMMD1 expression in individual samples from normal tissues or the corresponding cancer is shown (as normalized expression in log2 scale). Comparisons between groups were performed using the Student’s t test, with P values indicated in each panel. Panc duct, pancreatic duct. (C) Lack of detectable COMMD1 protein expression is frequent in ovarian cancer. Representative examples of COMMD1 immunohistochemical (IHC) staining of ovarian cancer specimens are shown (original magnification, ×200 [top panels]; ×600 [insets]; ×400 [bottom panels]). (D) COMMD1 expression in stromal cells from normal breast tissue and breast cancer is shown in a similar format as in A. (E) COMMD1 expression in normal prostate, prostate cancer, and metastatic prostate cancer specimens from lymph nodes is shown. Comparisons between groups were performed using the Student’s t test, with P values indicated. (F) COMMD1 expression in the same sample set, this time subdivided according to the local tumor T stage. Similar to A, the Student’s t test was performed to compare the groups, and P values are shown. (G) COMMD1 expression by immunohistochemical staining correlates with patient survival in endometrial cancer (n = 63). The survival curves of patients with intense cytoplasmic staining (high, blue curve) and weak/absent nucleocytoplasmic staining (low, red curve) are compared. Representative images (original magnification, ×400) are included.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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