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CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-κB

Oncogene volume 28, pages 2643–2653 (2009)Cite this article

Abstract

The mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger domains) is silenced in various human cancers by promoter hypermethylation, suggesting that CHFR is a tumor suppressor. Here, we show that CHFR functions as a negative regulator of the nuclear factor-κB (NF-κB) pathway. Expression of CHFR inhibited NF-κB reporter activity, whereas knockdown of CHFR activated reporter activity. These activities are independent of its RING finger domain. Furthermore, we found that CHFR physically interacts with p65 in cells. Electrophoretic mobility shift assays (EMSAs) and ELISA-based NF-κB-binding assays showed that CHFR negatively regulated transcriptional activity of p65. In addition, our data show that interleukin (IL)-8 is significantly downregulated by CHFR, and that the migration of human endothelial cells is suppressed in culture medium conditioned from CHFR-expressing cancer cells. Using a xenograft model, we show that neovascularization is suppressed by adenovirus-mediated transfer of CHFR. These results indicate that expression of CHFR markedly reduces the expression of IL-8 through the inhibition of NF-κB. As the NF-κB signaling pathway plays a critical role in the development and progression of cancer, our findings show the functional relationship between epigenetic alteration and inflammation/angiogenesis in human cancer cells, thereby showing several potential targets for therapeutic intervention.

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Acknowledgements

This research was supported by a grant to TT (KAKENHI (20390519)) from the Grants-in-Aid for Scientific Research (B) program of the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT). We thank Dr Toshiharu Suzuki (Hokkaido University, Japan) for the pcDNA3-Flag-p65 construct.

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Authors and Affiliations

  1. Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan

    L Kashima, M Toyota, H Mita, H Suzuki, M Idogawa, K Ogi, Y Sasaki & T Tokino

  2. First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan

    M Toyota & H Suzuki

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  1. L Kashima
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  2. M Toyota
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Correspondence to T Tokino.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Kashima, L., Toyota, M., Mita, H. et al. CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-κB. Oncogene 28, 2643–2653 (2009). https://doi.org/10.1038/onc.2009.123

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