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

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 fulllength 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 alpha (PGC-1 alpha/ERR alpha) pathway for mitochondrial biogenesis by reducing p53-dependent PGC-1 alpha 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-1 alpha/ERR alpha 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-1 alpha/ERR alpha axis has implications for predicting and targeting treatment resistance in OPSCC.

Automated summary

Therapy with radiation plus cisplatin kills HPV+ oropharyngeal squamous cell carcinomas (OPSCCs) by increasing reactive oxygen species beyond cellular antioxidant capacity. However, this standard treatment fails for some patients, and this study explores the potential role of HPV oncoprotein levels in affecting mitochondrial metabolism and treatment resistance. The results show that higher levels of the HPV oncoprotein fl-E6 are associated with reduced oxidative phosphorylation, antioxidant capacity and therapy resistance. Ectopically expressing fl-E6 in models with low baseline levels further depletes mitochondrial mass, sensitizes to therapy, and represses the alpha pathway for mitochondrial biogenesis. Clinical data supports these findings, with tumors expressing lower levels of fl-E6 displaying higher p53 target gene expression and an activated PGC-1 alpha/ERR alpha pathway, as well as reduced patient survival. These findings suggest that low levels of the HPV oncoprotein E6 can negatively affect treatment response and patient survival, and highlight the importance of considering the E6- PGC-1 alpha/ERR alpha axis in predicting and targeting treatment resistance in OPSCC.