HPV E6 regulates therapy responses in oropharyngeal cancer by repressing the PGC-1α/ERRα axis

JCI Insight. 2022 Sep 22;7(18):e159600. doi: 10.1172/jci.insight.159600.

Abstract

Therapy with radiation plus cisplatin kills HPV+ oropharyngeal squamous cell carcinomas (OPSCCs) by increasing reactive oxygen species beyond cellular antioxidant capacity. To explore why these standard treatments fail for some patients, we evaluated whether the variation in HPV oncoprotein levels among HPV+ OPSCCs affects mitochondrial metabolism, a source of antioxidant capacity. In cell line and patient-derived xenograft models, levels of HPV full-length E6 (fl-E6) inversely correlated with oxidative phosphorylation, antioxidant capacity, and therapy resistance, and fl-E6 was the only HPV oncoprotein to display such correlations. Ectopically expressing fl-E6 in models with low baseline levels reduced mitochondrial mass, depleted antioxidant capacity, and sensitized to therapy. In this setting, fl-E6 repressed the peroxisome proliferator-activated receptor gamma co-activator 1α/estrogen-related receptor α (PGC-1α/ERRα) pathway for mitochondrial biogenesis by reducing p53-dependent PGC-1α transcription. Concordant observations were made in 3 clinical cohorts, where expression of mitochondrial components was higher in tumors of patients with reduced survival. These tumors contained the lowest fl-E6 levels, the highest p53 target gene expression, and an activated PGC-1α/ERRα pathway. Our findings demonstrate that E6 can potentiate treatment responses by depleting mitochondrial antioxidant capacity and provide evidence for low E6 negatively affecting patient survival. E6's interaction with the PGC-1α/ERRα axis has implications for predicting and targeting treatment resistance in OPSCC.

Keywords: Head and neck cancer; Oncology; Therapeutics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antioxidants / metabolism
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use
  • ERRalpha Estrogen-Related Receptor
  • Humans
  • Oropharyngeal Neoplasms* / therapy
  • PPAR gamma / metabolism
  • Papillomavirus Infections* / complications
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
  • Reactive Oxygen Species / metabolism
  • Receptors, Estrogen
  • Transcription Factors / genetics
  • Tumor Suppressor Protein p53

Substances

  • Antioxidants
  • PPAR gamma
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Reactive Oxygen Species
  • Receptors, Estrogen
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Cisplatin