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

• Published in: Oncogene Vol. 28; no. 39; pp. 3499 - 3512
• Main Authors: Klanrit, P, Taebunpakul, P, Flinterman, M B, Odell, E W, Riaz, M A, Melino, G, Salomoni, P, Mymryk, J S, Gäken, J, Farzaneh, F, Tavassoli, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2009; Nature Publishing Group
• Subjects: Adenovirus E1A Proteins - metabolism; Ageing, cell death; Apoptosis; Biological and medical sciences; Cell Biology; Cell cycle; Cell death; Cell Line; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; DNA-Binding Proteins; Ectopic expression; Epidermal growth factor; Epidermal growth factor receptors; Fundamental and applied biological sciences. Psychology; Genetic aspects; Genetic regulation; Genetics; Growth factor receptors; Head & neck cancer; Head and neck cancer; Head and neck carcinoma; Head and Neck Neoplasms - metabolism; Human Genetics; Humans; Internal Medicine; Kinases; Lung cancer; Medical sciences; Medicine; Medicine & Public Health; Molecular and cellular biology; Nuclear Proteins - metabolism; Oncology; original-article; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; p53 Protein; Physiological aspects; Promyelocytic Leukemia Protein; Protein-tyrosine kinase; Receptor, Epidermal Growth Factor - metabolism; Squamous cell carcinoma; Transcription factors; Transcription Factors - metabolism; Transcription, Genetic; Tumor cell lines; Tumor Protein p73; Tumor Suppressor Proteins - metabolism; Tumors; Canada; United Kingdom; E1A; p73; HNSCC; PML; EGFR; Induction; Suppression; Malignant tumor; Carcinogenesis; ENT disease; Head and neck cancer; Cancer; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.191

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.