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HPV E6 regulates therapy responses in oropharyngeal cancer by repressing the PGC-1α/ERRα axis
Malay K. Sannigrahi, … , Elizabeth A. White, Devraj Basu
Malay K. Sannigrahi, … , Elizabeth A. White, Devraj Basu
Published September 22, 2022
Citation Information: JCI Insight. 2022;7(18):e159600. https://doi.org/10.1172/jci.insight.159600.
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Research Article Oncology Therapeutics

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

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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.

Authors

Malay K. Sannigrahi, Pavithra Rajagopalan, Ling Lai, Xinyi Liu, Varun Sahu, Hiroshi Nakagawa, Jalal B. Jalaly, Robert M. Brody, Iain M. Morgan, Bradford E. Windle, Xiaowei Wang, Phyllis A. Gimotty, Daniel P. Kelly, Elizabeth A. White, Devraj Basu

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Figure 7

PGC-1α/ERRα axis activation in tumors with high mitochondrial mass and therapy resistance.

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PGC-1α/ERRα axis activation in tumors with high mitochondrial mass and t...
PGC-1α was measured in HPV+ OPSCC PDXs by qRT-qPCR normalized to 18S. All other transcripts were measured by RNA-Seq. Pearson correlation coefficients for scatterplots were used to calculate r values with confidence intervals, and P values were determined by t distribution. (A) PDX PGC-1α mRNA versus the number of upregulated Hallmark_Oxidative_Phosphorylation transcripts (left) and versus mitochondrial mass (right) (MT-CO1/B2M by DNA qPCR). (B) PDX PGC-1α versus fl-E6 mRNA (left), p53 levels from Western blot densitometry (middle), and in vivo cisplatin response by rate-based T/C (right). (C) ERRα mRNA versus number of upregulated Hallmark_Oxidative_Phosphorylation transcripts in the PDXs (left) and the HPV+ OPSCCs in TCGA cohort (middle) and the JHU cohort (right). (D) Fl-E6 versus ERRα mRNA in TCGA cohort. (E) ERRα mRNA versus number of up-regulated Hallmark_P53_Pathway transcripts in TCGA cohort (left) and the JHU cohort (right).

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