c-MYC-dependent transcriptional inhibition of autophagy is implicated in cisplatin sensitivity in HPV-positive head and neck cancer.
Alessandro MeddaMicaela CompagnoniGiorgio SpiniSimona CitroOttavio CrociStefano CampanerMarta TagliabueMohssen AnsarinSusanna ChioccaPublished in: Cell death & disease (2023)
Autophagy is important for the removal, degradation and recycling of damaged organelles, proteins, and lipids through the degradative action of lysosomes. In addition to its catabolic function, autophagy is important in cancer and viral-mediated tumorigenesis, including Human Papillomavirus (HPV) positive cancers. HPV infection is a major risk factor in a subset of head and neck cancer (HNC), for which no targeted therapies are currently available. Herein, we assessed autophagy function in HPV-positive HNC. We showed that HPV-positive HNC cells presented a transcriptional and functional impairment of the autophagic process compared to HPV-negative cells, which were reactivated by knocking down HPV E6/E7 oncoproteins, the drivers of cellular transformation. We found that the oncoprotein c-MYC was stabilized and triggered in HPV-positive cell lines. This resulted in the reduced binding of the MiT/TFE transcription factors to their autophagy targets due to c-MYC competition. Thus, the knock-down of c-MYC induced the upregulation of autophagic and lysosomal genes in HPV-positive HNC cells, as well as the increase of autophagic markers at the protein level. Moreover, HPV oncoprotein E7 upregulated the expression of the phosphatase inhibitor CIP2A, accounting for c-MYC upregulation and stability in HPV+ HNC cells. CIP2A mRNA expression negatively correlated with autophagy gene expression in tumor tissues from HNC patients, showing, for the first time, its implication in a transcriptional autophagic context. Both CIP2A and c-MYC knock-down, as well as pharmacological downregulation of c-MYC, resulted in increased resistance to cisplatin treatment. Our results not only show a novel way by which HPV oncoproteins manipulate the host machinery but also provide more insights into the role of autophagy in chemoresistance, with possible implications for targeted HPV-positive HNC therapy.
Keyphrases
- cell death
- high grade
- gene expression
- induced apoptosis
- cell cycle arrest
- endoplasmic reticulum stress
- signaling pathway
- oxidative stress
- cervical cancer screening
- transcription factor
- poor prognosis
- risk factors
- end stage renal disease
- chronic kidney disease
- stem cells
- dna methylation
- squamous cell carcinoma
- bone marrow
- cell proliferation
- small molecule
- cell therapy
- newly diagnosed
- fatty acid
- mesenchymal stem cells
- prognostic factors
- drug delivery
- endothelial cells
- dna binding
- cancer therapy
- combination therapy
- replacement therapy