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HDAC3 represses the expression of NKG2D ligands ULBPs in epithelial tumour cells: potential implications for the immunosurveillance of cancer

Oncogene volume 28, pages 2370–2382 (2009)Cite this article

Abstract

The expression of the NKG2D ligands on cancer cells leads to their recognition and elimination by host immune responses mediated by natural killer and T cells. UL16-binding proteins (ULBPs) are NKG2D ligands, which are scarcely expressed in epithelial tumours, favouring their evasion from the immune system. Herein, we investigated the epigenetic mechanisms underlying the repression of ULBPs in epithelial cancer cells. We show that ULBP1–3 expression is increased in tumour cells after exposure to the inhibitor of histone deacetylases (HDACs) trichostatin A (TSA), which enhances the natural killer cell-mediated cytotoxicity of HeLa cells. Our experiments showed that the transcription factor Sp3 is crucial in the activation of the ULBP1 promoter by TSA. Furthermore, by small interfering RNA-mediated knockdown and overexpression of HDAC1–3, we showed that HDAC3 is a repressor of ULBPs expression in epithelial cancer cells. Remarkably, TSA treatment caused the complete release of HDAC3 from the ULBP1–3 promoters. HDAC3 is recruited to the ULBP1 promoter through its interaction with Sp3 and TSA treatment interfered with this association. Together, we describe a new mechanism by which cancer cells may evade the immune response through the epigenetic modulation of the ULBPs expression and provide a model in which HDAC inhibitors may favour the elimination of transformed cells by increasing the immunogenicity of epithelial tumours.

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Acknowledgements

We thank Dr Spies and Amgen for kindly providing ULBP antibodies, Dr García de Herreros for providing HT-29 M6 cells, Banco de Tumores del Hospital Universitario Central de Asturias for providing human tumour samples, Dr G Gill for providing the pBS/U6-Scrambled plasmid, Dr A Astudillo for histopathological evaluation, Dr C López-Otín for helpful comments and A Vallina and MS Pitiot for technical assistance. This work was supported by the Spanish grants of Fondo de Investigaciones Sanitarias PI-06/0841. ALS holds a predoctoral fellowship from FICYT of Asturias (BP06-99).

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Authors and Affiliations

  1. Departamento de Biología Funcional, Universidad de Oviedo, IUOPA, Principado de Asturias, Spain

    A López-Soto & S Gonzalez

  2. Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, IUOPA, Principado de Asturias, Spain

    A R Folgueras

  3. H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    E Seto

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  1. A López-Soto
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  2. A R Folgueras
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Correspondence to S Gonzalez.

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

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López-Soto, A., Folgueras, A., Seto, E. et al. HDAC3 represses the expression of NKG2D ligands ULBPs in epithelial tumour cells: potential implications for the immunosurveillance of cancer. Oncogene 28, 2370–2382 (2009). https://doi.org/10.1038/onc.2009.117

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