PTPRT epigenetic silencing defines lung cancer with STAT3 activation and can direct STAT3 targeted therapies
Signal Transducers and Activators of Transcription-3 (STAT3), a potent oncogenic transcription factor, is constitutively activated in lung cancer, but mutations in pathway genes are infrequent. Protein Tyrosine Phosphatase Receptor-T (PTPRT) is an endogenous inhibitor of STAT3 and PTPRT loss-of-func...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-07-01
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| Series: | Epigenetics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15592294.2019.1676597 |
| _version_ | 1797678874617708544 |
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| author | Malabika Sen Audrey Kindsfather Ludmila Danilova Feng Zhang Raffaele Colombo Matthew G. LaPorte Brenda F. Kurland Donna M. Huryn Peter Wipf James G. Herman |
| author_facet | Malabika Sen Audrey Kindsfather Ludmila Danilova Feng Zhang Raffaele Colombo Matthew G. LaPorte Brenda F. Kurland Donna M. Huryn Peter Wipf James G. Herman |
| author_sort | Malabika Sen |
| collection | DOAJ |
| description | Signal Transducers and Activators of Transcription-3 (STAT3), a potent oncogenic transcription factor, is constitutively activated in lung cancer, but mutations in pathway genes are infrequent. Protein Tyrosine Phosphatase Receptor-T (PTPRT) is an endogenous inhibitor of STAT3 and PTPRT loss-of-function represents one potential mechanism of STAT3 hyperactivation as observed in other malignancies. We determined the role of PTPRT promoter methylation and sensitivity to STAT3 pathway inhibitors in non-small cell lung cancer (NSCLC). TCGA and Pittsburgh lung cancer cohort methylation data revealed hypermethylation of PTPRT associated with diminished mRNA expression in a subset of NSCLC patients. We report frequent hypermethylation of the PTPRT promoter which correlates with transcriptional silencing of PTPRT and increased STAT3 phosphorylation (Y705) as determined by methylation-specific PCR (MSP) and real time quantitative reverse transcription (RT)-PCR in NSCLC cell lines. Silencing of PTPRT using siRNA in H520 lung cancer cell line resulted in increased pSTAT3Tyr705 and upregulation of STAT3 target genes such as Cyclin D1 and Bcl-XL expression. We show this association of PRPRT methylation with upregulation of the STAT3 target genes Cyclin D1 and Bcl-XL in patient derived lung tumour samples. We further demonstrate that PTPRT promoter methylation associated with different levels of pSTAT3Ty705 in lung cancer cell lines had selective sensitivity to STAT3 pathway small molecule inhibitors (SID 864,669 and SID 4,248,543). Our data strongly suggest that silencing of PTPRT by promoter hypermethylation is an important mechanism of STAT3 hyperactivation and targeting STAT3 may be an effective approach for the development of new lung cancer therapeutics. |
| first_indexed | 2024-03-11T23:06:16Z |
| format | Article |
| id | doaj.art-333860db35804967959dcc5164891d1b |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:06:16Z |
| publishDate | 2020-07-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-333860db35804967959dcc5164891d1b2023-09-21T13:09:22ZengTaylor & Francis GroupEpigenetics1559-22941559-23082020-07-01156-760461710.1080/15592294.2019.16765971676597PTPRT epigenetic silencing defines lung cancer with STAT3 activation and can direct STAT3 targeted therapiesMalabika Sen0Audrey Kindsfather1Ludmila Danilova2Feng Zhang3Raffaele Colombo4Matthew G. LaPorte5Brenda F. Kurland6Donna M. Huryn7Peter Wipf8James G. Herman9UPMC Hillman Cancer CenterUPMC Hillman Cancer CenterJohns Hopkins University School of MedicineUniversity of PittsburghUniversity of PittsburghUniversity of PittsburghUniversity of PittsburghUniversity of PittsburghUniversity of PittsburghUPMC Hillman Cancer CenterSignal Transducers and Activators of Transcription-3 (STAT3), a potent oncogenic transcription factor, is constitutively activated in lung cancer, but mutations in pathway genes are infrequent. Protein Tyrosine Phosphatase Receptor-T (PTPRT) is an endogenous inhibitor of STAT3 and PTPRT loss-of-function represents one potential mechanism of STAT3 hyperactivation as observed in other malignancies. We determined the role of PTPRT promoter methylation and sensitivity to STAT3 pathway inhibitors in non-small cell lung cancer (NSCLC). TCGA and Pittsburgh lung cancer cohort methylation data revealed hypermethylation of PTPRT associated with diminished mRNA expression in a subset of NSCLC patients. We report frequent hypermethylation of the PTPRT promoter which correlates with transcriptional silencing of PTPRT and increased STAT3 phosphorylation (Y705) as determined by methylation-specific PCR (MSP) and real time quantitative reverse transcription (RT)-PCR in NSCLC cell lines. Silencing of PTPRT using siRNA in H520 lung cancer cell line resulted in increased pSTAT3Tyr705 and upregulation of STAT3 target genes such as Cyclin D1 and Bcl-XL expression. We show this association of PRPRT methylation with upregulation of the STAT3 target genes Cyclin D1 and Bcl-XL in patient derived lung tumour samples. We further demonstrate that PTPRT promoter methylation associated with different levels of pSTAT3Ty705 in lung cancer cell lines had selective sensitivity to STAT3 pathway small molecule inhibitors (SID 864,669 and SID 4,248,543). Our data strongly suggest that silencing of PTPRT by promoter hypermethylation is an important mechanism of STAT3 hyperactivation and targeting STAT3 may be an effective approach for the development of new lung cancer therapeutics.http://dx.doi.org/10.1080/15592294.2019.1676597ptprt methylationstat3non-small cell lung cancer |
| spellingShingle | Malabika Sen Audrey Kindsfather Ludmila Danilova Feng Zhang Raffaele Colombo Matthew G. LaPorte Brenda F. Kurland Donna M. Huryn Peter Wipf James G. Herman PTPRT epigenetic silencing defines lung cancer with STAT3 activation and can direct STAT3 targeted therapies Epigenetics ptprt methylation stat3 non-small cell lung cancer |
| title | PTPRT epigenetic silencing defines lung cancer with STAT3 activation and can direct STAT3 targeted therapies |
| title_full | PTPRT epigenetic silencing defines lung cancer with STAT3 activation and can direct STAT3 targeted therapies |
| title_fullStr | PTPRT epigenetic silencing defines lung cancer with STAT3 activation and can direct STAT3 targeted therapies |
| title_full_unstemmed | PTPRT epigenetic silencing defines lung cancer with STAT3 activation and can direct STAT3 targeted therapies |
| title_short | PTPRT epigenetic silencing defines lung cancer with STAT3 activation and can direct STAT3 targeted therapies |
| title_sort | ptprt epigenetic silencing defines lung cancer with stat3 activation and can direct stat3 targeted therapies |
| topic | ptprt methylation stat3 non-small cell lung cancer |
| url | http://dx.doi.org/10.1080/15592294.2019.1676597 |
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