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

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 ups...

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Autores principales: Peyser, Noah D., Freilino, Maria, Wang, Lin, Zeng, Yan, Li, Hua, Johnson, Daniel E., Grandis, Jennifer R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651851/
https://www.ncbi.nlm.nih.gov/pubmed/25982282
http://dx.doi.org/10.1038/onc.2015.171
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author Peyser, Noah D.
Freilino, Maria
Wang, Lin
Zeng, Yan
Li, Hua
Johnson, Daniel E.
Grandis, Jennifer R.
author_facet Peyser, Noah D.
Freilino, Maria
Wang, Lin
Zeng, Yan
Li, Hua
Johnson, Daniel E.
Grandis, Jennifer R.
author_sort Peyser, Noah D.
collection PubMed
description 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 (LOF) of negative regulators of STAT3, including by promoter hypermethylation of PTPRT. Here we first analyzed The Cancer Genome Atlas (TCGA) 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 (MSP) 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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spelling pubmed-46518512016-05-18 Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer Peyser, Noah D. Freilino, Maria Wang, Lin Zeng, Yan Li, Hua Johnson, Daniel E. Grandis, Jennifer R. Oncogene Article 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 (LOF) of negative regulators of STAT3, including by promoter hypermethylation of PTPRT. Here we first analyzed The Cancer Genome Atlas (TCGA) 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 (MSP) 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. 2015-05-18 2016-03-03 /pmc/articles/PMC4651851/ /pubmed/25982282 http://dx.doi.org/10.1038/onc.2015.171 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Peyser, Noah D.
Freilino, Maria
Wang, Lin
Zeng, Yan
Li, Hua
Johnson, Daniel E.
Grandis, Jennifer R.
Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer
title Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer
title_full Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer
title_fullStr Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer
title_full_unstemmed Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer
title_short Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer
title_sort frequent promoter hypermethylation of ptprt increases stat3 activation and sensitivity to stat3 inhibition in head and neck cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651851/
https://www.ncbi.nlm.nih.gov/pubmed/25982282
http://dx.doi.org/10.1038/onc.2015.171
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