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HOXB13 downregulates intracellular zinc and increases NF-κB signaling to promote prostate cancer metastasis

Oncogene volume 33, pages 4558–4567 (2014)Cite this article

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Abstract

Characteristically, prostate cancer (PCa) cells exhibit marked decrease in intracellular zinc; however, the mechanism responsible is not clearly understood. HOXB13 is involved in PCa progression and is overexpressed in castration-resistant PCa. DNA microarray analysis of LNCaP Pca cells showed that ZnT zinc output transporters were strikingly upregulated among androgen-independent HOXB13 target genes. Furthermore, exogenous HOXB13 caused intracellular zinc concentrations to fall in PCa cells, stimulated NF-κB-mediated signaling by reducing inhibitor of NF-κB alpha (IκBα) and enhanced the nuclear translocation of RelA/p65. Human prostate tumors also exhibited strong inverse correlation between the protein expressions of HOXB13 and IκBα. Consequently, HOXB13 stimulated PCa cell invasion, and this was inhibited by the suppression of ZnT4. In addition, studies in a PC3 orthotopic mouse model of PCa metastasis showed that HOXB13 is a strong metastatic stimulator. Taken together, these results show that HOXB13 promotes PCa invasion and metastasis by decreasing intracellular zinc levels, thus stimulating NF-κB signals, and suggest that HOXB13 acts as a modulator of intracellular zinc levels that promotes the malignant characteristics of PCa.

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Acknowledgements

This work was supported by the Korea Science and Engineering Foundation through the Medical Research Center for Gene Regulation (2012-0009445), by the Basic Science Research Program of the National Research Foundation of Korea (NRF) grant funded by the Korea Government (2010-0003838), and by a grant from the Chonnam National University Research Institute of Medical Sciences ((2010-CURIMS-DR011).

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Authors and Affiliations

  1. Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea

    Y-R Kim, I-J Kim, K I Nam & C Jung

  2. Department of Urology, Chonnam National University Medical School, Gwangju, Korea

    T W Kang

  3. Department of Pathology, Chonnam National University Medical School, Gwangju, Korea

    C Choi

  4. Department of Pharmacology, Chonnam National University Medical School, Gwangju, Korea

    K K Kim

  5. Department of Statistics, College of Natural Sciences, Chonnam National University, Gwangju, Korea

    M S Kim

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Kim, YR., Kim, IJ., Kang, T. et al. HOXB13 downregulates intracellular zinc and increases NF-κB signaling to promote prostate cancer metastasis. Oncogene 33, 4558–4567 (2014). https://doi.org/10.1038/onc.2013.404

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