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PML involvement in the p73-mediated E1A-induced suppression of EGFR and induction of apoptosis in head and neck cancers

Oncogene volume 28, pages 3499–3512 (2009)Cite this article

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase is commonly overexpressed in human cancers; however, the cellular mechanisms regulating EGFR expression remain unclear. p53, p63 and p73 are transcription factors regulating many cellular targets involved in controlling the cell cycle and apoptosis. p53 activates EGFR expression, whereas TAp63 represses EGFR transcription. The involvement of p73 in the regulation of EGFR has not been reported. Here, a strong correlation between EGFR overexpression and increased levels of the oncogenic ΔNp73 isoform in head and neck squamous cell carcinoma (HNSCC) cell lines was observed. Ectopic expression of TAp73, particularly TAp73β, resulted in suppression of the EGFR promoter, significant downregulation of EGFR protein and efficient induction of cell death in all six EGFR-overexpressing HNSCC cell lines. EGFR overexpression from a heterologous LTR promoter protected lung cancer cells from TAp73β-induced EGFR suppression and apoptosis. Expression of TAp73β efficiently induced promyelocytic leukaemia (PML) protein expression and PML knockdown by shRNA attenuated the downregulation of EGFR and induction of apoptosis by p73 in HNSCC cells. Furthermore, PML was found to be important for E1A-induced suppression of EGFR and subsequent killing of HNSCC cells. Our data therefore suggest a novel pathway involving PML and p73 in the regulation of EGFR expression.

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Acknowledgements

We thank Prof Bert Vogelstein for providing Ad-GFP-p53 and Ad-GFP, Prof Karen Vousden for providing Ad-GFP-TAp73β, Prof Alfred Johnson for providing pER1-luc and Associate Prof Kun-Sang Chang for anti-PML clone 3573 antibody. We also thank Prof Alan Lehmann for 1BR3 and 1BR3-LT, Prof Hugh Paterson for 6689, Prof Barry Gusterson for HN5, Prof Kazuya Tominaga for HSC-3 and HSC-3 M3, Prof Fiona Watts for Km3, Prof Andrew Yeudall for HN30 and Prof Stephen Prime for H103 and H357 cell lines. We especially thank Prof Christoph Borner for the critical and helpful reading of this paper. This work was supported by grants from Cancer Research UK, the Rosetrees Trust and Biomedical Research Centre at Guy's and St Thomas’ NHS Foundation Trust and King's College London. Marcella Flinterman was supported by a grant from Cancer Research UK (C1116). Poramaporn Klanrit and Patrayu Taebunpakul were supported by the Royal Thai Government Scholarship.

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Authors and Affiliations

  1. Head and Neck Oncology Group, King's College London Dental Institute, Guy's Hospital Campus, London, UK

    P Klanrit, P Taebunpakul, M B Flinterman, M A Riaz & M Tavassoli

  2. Department of Oral Pathology, King's College London Dental Institute, Guy's Hospital Campus, London, UK

    E W Odell

  3. Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK

    G Melino & P Salomoni

  4. Department of Oncology, London Regional Cancer Program, The University of Western Ontario, London, Ontario, Canada

    J S Mymryk

  5. Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada

    J S Mymryk

  6. Department of Hematological and Molecular Medicine, King's College London, London, UK

    J Gäken & F Farzaneh

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

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Klanrit, P., Taebunpakul, P., Flinterman, M. et al. PML involvement in the p73-mediated E1A-induced suppression of EGFR and induction of apoptosis in head and neck cancers. Oncogene 28, 3499–3512 (2009). https://doi.org/10.1038/onc.2009.191

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