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The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin–proteasome system

Oncogene volume 29, pages 1498–1508 (2010)Cite this article

Abstract

The inhibitor of growth family member 3 (ING3) has been shown to modulate transcription, cell cycle control and apoptosis. We previously reported that nuclear ING3 expression was remarkably reduced in melanomas, which correlated with a poorer patient survival, suggesting that decreased ING3 expression may be associated with melanoma progression. However, the mechanism of diminished ING3 expression in melanoma is not clear. Here we show that ING3 level was decreased in metastatic melanoma cells because of a rapid degradation. Furthermore, we showed that ING3 undergoes degradation through the ubiquitin–proteasome pathway. ING3 physically interacts with subunits of E3 ligase Skp1-Cullin-F-box protein complex (SCF complex). Knockdown of F-box protein S-phase kinase-associated protein 2 (Skp2) reduces the ubiquitination of ING3 and significantly stabilizes ING3 in melanoma cells. In addition, lysine 96 residue is essential for ING3 ubiquitination as its mutation to arginine dramatically abrogated ING3 degradation. Disruption of ING3 degradation stimulated ING3-induced G1 cell-cycle arrest and enhanced ultraviolet-induced apoptosis. Taken together, our data show that ING3 is degraded by the ubiquitin–proteasome pathway through the SCFSkp2 complex and interruption of ING3 degradation enhances the tumor-suppressive function of ING3, which provides a potential cancer therapeutic approach by interfering ING3 degradation.

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Acknowledgements

We gratefully thank Drs HR Byers, AP Albino, H Silver, R Zhang, M Pagano, S Sun and J Hsieh for kindly providing the materials. This study was supported by Cancer Research Society, the Canadian Institutes of Health Research (MOP-93810) and the Canadian Dermatology Foundation (GL). GC is a recipient of Postdoctoral Trainee Award from Michael Smith Foundation for Health Research. YW is a recipient of Roman M Babicki Fellowship from the University of British Columbia and a research fellow of the Terry Fox Foundation through an award from the National Cancer Institute of Canada.

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Author notes

  1. G Chen and Y Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada

    G Chen, Y Wang, M Garate & G Li

  2. Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, Nanjing, PR China

    J Zhou

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  1. G Chen
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Correspondence to G Li.

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

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Chen, G., Wang, Y., Garate, M. et al. The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin–proteasome system. Oncogene 29, 1498–1508 (2010). https://doi.org/10.1038/onc.2009.424

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