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ING4 regulates a secretory phenotype in primary fibroblasts with dual effects on cell proliferation and tumor growth

Oncogene volume 33, pages 1945–1953 (2014)Cite this article

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Abstract

ING proteins have an essential role in the control of a variety of cellular functions whose deregulation is associated with tumor formation and dissemination, such as proliferation, apoptosis, senescence or invasion. Accordingly, loss of function of ING proteins is a frequent event in many types of human tumors. In this report, we have studied the function of ING4, a member of the ING family of tumor suppressors, in the context of normal, non-transformed primary fibroblasts. We show that ING4 negatively regulates cell proliferation in this cell type. The antiproliferative action of ING4 requires its ability to recognize chromatin marks, it is p53-dependent at least in part, and it is lost in an ING4 cancer-associated mutant. Gene expression analysis shows that ING4 regulates the expression and release of soluble factors of the chemokine family. The secretory phenotype regulated by ING4 in primary fibroblasts displays a selective paracrine effect on proliferation, fostering the division of tumor cells, while inhibiting division in primary fibroblasts. Consistently, ING4-expressing fibroblasts promoted tumor growth in vivo in co-injection tumorigenesis assays. Collectively, our results show that ING4 not only can regulate the proliferation of primary non-transformed human fibroblasts, but also orchestrates a secretory phenotype in these cells that promotes tumor cell proliferation in vitro and in vivo. These findings support a critical role for ING4 expression in normal cells in the non-cell-autonomous regulation of tumor growth.

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Acknowledgements

We thank R Gomis, J Massague, G Peters, D Peeper and A Cano for providing cell lines and reagents, V Miguel for help in some experiments and I Peruzza for technical assistance. This work was supported by grants from the Spanish Ministry of Science and Innovation to IP (SAF2009-09031 and SAF2012-32117) and GM-B (SAF2010-20175), and from the Madrid Regional Government (S2010/BMD-2303) to GM-B.

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Author notes

  1. A Moreno

    Present address: 3Current address: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, UK.,

  2. I Soleto and P García-Sanz: These authors contributed equally to this work.

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas ‘Alberto Sols’ CSIC-UAM, Madrid, Spain

    A Moreno, I Soleto, P García-Sanz, G Moreno-Bueno & I Palmero

  2. Departamento de Bioquímica, Universidad Autónoma de Madrid, IdiPAZ (Instituto de Investigación Sanitaria La Paz) and Fundación MD Anderson Internacional, Madrid, Spain

    P García-Sanz & G Moreno-Bueno

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Correspondence to I Palmero.

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Moreno, A., Soleto, I., García-Sanz, P. et al. ING4 regulates a secretory phenotype in primary fibroblasts with dual effects on cell proliferation and tumor growth. Oncogene 33, 1945–1953 (2014). https://doi.org/10.1038/onc.2013.145

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