EGFR-induced suppression of HPV E6/E7 is mediated by microRNA-9-5p silencing of BRD4 protein in HPV-positive head and neck squamous cell carcinoma

Autor: Danupon Nantajit, Luana Presta, Thomas Sauter, Mahvash Tavassoli
Rok vydání: 2022
Předmět:
Cancer Research
Papillomavirus E7 Proteins
Immunology
Squamous Cell Carcinoma of Head and Neck/genetics
Cell Cycle Proteins
Multidisciplinary
general & others [F99] [Life sciences]
MicroRNAs/genetics/therapeutic use
Cellular and Molecular Neuroscience
Multidisciplinaire
généralités & autres [F99] [Sciences du vivant]
Cell Line
Tumor
Humans
Cell Cycle Proteins/genetics
Squamous Cell Carcinoma of Head and Neck
Repressor Proteins/metabolism
Papillomavirus Infections
Oncogene Proteins
Viral/genetics/metabolism
Nuclear Proteins
Head and Neck Neoplasms/genetics
Cell Biology
Nuclear Proteins/genetics/therapeutic use
Oncogene Proteins
Viral
Carcinoma
Squamous Cell/pathology
Transcription Factors/genetics/therapeutic use
ErbB Receptors/genetics/metabolism
Repressor Proteins
ErbB Receptors
MicroRNAs
Head and Neck Neoplasms
Carcinoma
Squamous Cell
Papillomavirus E7 Proteins/genetics/metabolism
Transcription Factors
Zdroj: Cell deathdisease. 13(11)
ISSN: 2041-4889
Popis: EGFR upregulation is an established biomarker of treatment resistance and aggressiveness in head and neck cancers (HNSCC). EGFR-targeted therapies have shown benefits for HPV-negative HNSCC; surprisingly, inhibiting EGFR in HPV-associated HNSCC led to inferior therapeutic outcomes suggesting opposing roles for EGFR in the two HNSCC subtypes. The current study aimed to understand the link between EGFR and HPV-infected HNSCC particularly the regulation of HPV oncoproteins E6 and E7. We demonstrate that EGFR overexpression suppresses cellular proliferation and increases radiosensitivity of HPV-positive HNSCC cell lines. EGFR overexpression inhibited protein expression of BRD4, a known cellular transcriptional regulator of HPV E6/E7 expression and DNA damage repair facilitator. Inhibition of EGFR by cetuximab restored the expression of BRD4 leading to increased HPV E6 and E7 transcription. Concordantly, pharmacological inhibition of BRD4 led to suppression of HPV E6 and E7 transcription, delayed cellular proliferation and sensitised HPV-positive HNSCC cells to ionising radiation. This effect was shown to be mediated through EGFR-induced upregulation of microRNA-9-5p and consequent silencing of its target BRD4 at protein translational level, repressing HPV E6 and E7 transcription and restoring p53 tumour suppressor functions. These results suggest a novel mechanism for EGFR inhibition of HPV E6/E7 oncoprotein expression through an epigenetic pathway, independent of MAPK, but mediated through microRNA-9-5p/BRD4 regulation. Therefore, targeting EGFR may not be the best course of therapy for certain cancer types including HPV-positive HNSCC, while targeting specific signalling pathways such as BRD4 could provide a better and potentially new treatment to improve HNSCC therapeutic outcome.
Databáze: OpenAIRE
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