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Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer

Oncogene volume 35, pages 1163–1169 (2016)Cite this article

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Abstract

Signal transducer and activator of transcription 3 (STAT3) overactivation is a common event in many cancers, including head and neck squamous cell carcinoma (HNSCC), where STAT3 represents a promising therapeutic target. HNSCC is not characterized by frequent kinase mutations, in contrast to some malignancies where mutational activation of kinases upstream of STAT3 is common. Instead, STAT3 may be activated by loss-of-function of negative regulators of STAT3, including by promoter hypermethylation of PTPRT. Here we first analyzed The Cancer Genome Atlas data and determined that the PTPRT promoter is frequently hypermethylated in several cancers, including HNSCC (60.1% of tumors analyzed) in association with downregulation of PTPRT mRNA expression and upregulation of pSTAT3 expression. These findings were confirmed in an independent cohort of HNSCC tumors by methylation-specific PCR and immunohistochemistry. We demonstrate that PTPRT promoter methylation and gene silencing is reversible in HNSCC cells, leading to PTPRT-specific downregulation of pSTAT3 expression. We further show that PTPRT promoter methylation is significantly associated with sensitivity to STAT3 inhibition in HNSCC cells, suggesting that PTPRT promoter methylation may serve as a predictive biomarker for responsiveness to STAT3 inhibitors in clinical development.

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Acknowledgements

This work was supported by the National Cancer Institute at the National Institutes of Health (grant numbers P50 CA097190 and R01 CA077308 to JRG); and by the National Institute for Dental and Craniofacial Research at the National Institutes of Health (grant number F31 DE024007 to NDP). The authors wish to thank Mark H Gage for technical assistance.

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Authors and Affiliations

  1. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    N D Peyser & D E Johnson

  2. Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    N D Peyser, M Freilino, L Wang, Y Zeng & H Li

  3. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    D E Johnson

  4. Department of Otolaryngology, University of California, San Francisco, CA, USA

    J R Grandis

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  1. N D Peyser
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  2. M Freilino
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Correspondence to J R Grandis.

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Peyser, N., Freilino, M., Wang, L. et al. Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer. Oncogene 35, 1163–1169 (2016). https://doi.org/10.1038/onc.2015.171

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  • DOI: https://doi.org/10.1038/onc.2015.171

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