title: Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer.
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.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: N D
authors.initials: ND
authors.lastname: Peyser
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Freilino
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Johnson
authors.affiliation: Department of Otolaryngology, University of California, San Francisco, CA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D011401:Promoter Regions, Genetic; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C516865:PTPRT protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2