Chromatin-Independent Interplay of NFATc1 and EZH2 in Pancreatic Cancer
Background: The Nuclear Factor of Activated T-cells 1 (NFATc1) transcription factor and the methyltransferase Enhancer of Zeste Homolog 2 (EZH2) significantly contribute to the aggressive phenotype of pancreatic ductal adenocarcinoma (PDAC). Herein, we aimed at dissecting the mechanistic background...
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MDPI AG
2021-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/12/3463 |
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| author | Shilpa Patil Teresa Forster Kristina Reutlinger Waltraut Kopp Lennart Versemann Jessica Spitalieri Jochen Gaedcke Philipp Ströbel Shiv K. Singh Volker Ellenrieder Albrecht Neesse Elisabeth Hessmann |
| author_facet | Shilpa Patil Teresa Forster Kristina Reutlinger Waltraut Kopp Lennart Versemann Jessica Spitalieri Jochen Gaedcke Philipp Ströbel Shiv K. Singh Volker Ellenrieder Albrecht Neesse Elisabeth Hessmann |
| author_sort | Shilpa Patil |
| collection | DOAJ |
| description | Background: The Nuclear Factor of Activated T-cells 1 (NFATc1) transcription factor and the methyltransferase Enhancer of Zeste Homolog 2 (EZH2) significantly contribute to the aggressive phenotype of pancreatic ductal adenocarcinoma (PDAC). Herein, we aimed at dissecting the mechanistic background of their interplay in PDAC progression. Methods: NFATc1 and EZH2 mRNA and protein expression and complex formation were determined in transgenic PDAC models and human PDAC specimens. NFATc1 binding on the <i>Ezh2</i> gene and the consequences of perturbed NFATc1 expression on <i>Ezh2</i> transcription were explored by Chromatin Immunoprecipitation (ChIP) and upon transgenic or siRNA-mediated interference with NFATc1 expression, respectively. Integrative analyses of RNA- and ChIP-seq data was performed to explore NFATc1-/EZH2-dependent gene signatures. Results: NFATc1 targets the <i>Ezh2</i> gene for transcriptional activation and biochemically interacts with the methyltransferase in murine and human PDAC. Surprisingly, our genome-wide binding and expression analyses do not link the protein complex to joint gene regulation. In contrast, our findings provide evidence for chromatin-independent functions of the NFATc1:EZH2 complex and reveal posttranslational EZH2 phosphorylation at serine 21 as a prerequisite for robust complex formation. Conclusion: Our findings disclose a previously unknown NFATc1-EZH2 axis operational in the pancreas and provide mechanistic insights into the conditions fostering NFATc1:EZH2 complex formation in PDAC. |
| first_indexed | 2024-03-10T04:26:12Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T04:26:12Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-cf79afc6f51f479caa2c7e51b44a27b42023-11-23T07:38:07ZengMDPI AGCells2073-44092021-12-011012346310.3390/cells10123463Chromatin-Independent Interplay of NFATc1 and EZH2 in Pancreatic CancerShilpa Patil0Teresa Forster1Kristina Reutlinger2Waltraut Kopp3Lennart Versemann4Jessica Spitalieri5Jochen Gaedcke6Philipp Ströbel7Shiv K. Singh8Volker Ellenrieder9Albrecht Neesse10Elisabeth Hessmann11Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, GermanyDepartment of Gastroenterology, Endocrinology, Metabolism and Clinical Infectiology, Philipps University Marburg, 35043 Marburg, GermanyDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, GermanyDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, GermanyDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, GermanyDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, GermanyClinical Research Unit KFO5002, University Medical Center Goettingen, 37075 Goettingen, GermanyClinical Research Unit KFO5002, University Medical Center Goettingen, 37075 Goettingen, GermanyDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, GermanyDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, GermanyDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, GermanyDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, GermanyBackground: The Nuclear Factor of Activated T-cells 1 (NFATc1) transcription factor and the methyltransferase Enhancer of Zeste Homolog 2 (EZH2) significantly contribute to the aggressive phenotype of pancreatic ductal adenocarcinoma (PDAC). Herein, we aimed at dissecting the mechanistic background of their interplay in PDAC progression. Methods: NFATc1 and EZH2 mRNA and protein expression and complex formation were determined in transgenic PDAC models and human PDAC specimens. NFATc1 binding on the <i>Ezh2</i> gene and the consequences of perturbed NFATc1 expression on <i>Ezh2</i> transcription were explored by Chromatin Immunoprecipitation (ChIP) and upon transgenic or siRNA-mediated interference with NFATc1 expression, respectively. Integrative analyses of RNA- and ChIP-seq data was performed to explore NFATc1-/EZH2-dependent gene signatures. Results: NFATc1 targets the <i>Ezh2</i> gene for transcriptional activation and biochemically interacts with the methyltransferase in murine and human PDAC. Surprisingly, our genome-wide binding and expression analyses do not link the protein complex to joint gene regulation. In contrast, our findings provide evidence for chromatin-independent functions of the NFATc1:EZH2 complex and reveal posttranslational EZH2 phosphorylation at serine 21 as a prerequisite for robust complex formation. Conclusion: Our findings disclose a previously unknown NFATc1-EZH2 axis operational in the pancreas and provide mechanistic insights into the conditions fostering NFATc1:EZH2 complex formation in PDAC.https://www.mdpi.com/2073-4409/10/12/3463chromatinEZH2NFATc1pancreatic cancerposttranslational EZH2 modification |
| spellingShingle | Shilpa Patil Teresa Forster Kristina Reutlinger Waltraut Kopp Lennart Versemann Jessica Spitalieri Jochen Gaedcke Philipp Ströbel Shiv K. Singh Volker Ellenrieder Albrecht Neesse Elisabeth Hessmann Chromatin-Independent Interplay of NFATc1 and EZH2 in Pancreatic Cancer Cells chromatin EZH2 NFATc1 pancreatic cancer posttranslational EZH2 modification |
| title | Chromatin-Independent Interplay of NFATc1 and EZH2 in Pancreatic Cancer |
| title_full | Chromatin-Independent Interplay of NFATc1 and EZH2 in Pancreatic Cancer |
| title_fullStr | Chromatin-Independent Interplay of NFATc1 and EZH2 in Pancreatic Cancer |
| title_full_unstemmed | Chromatin-Independent Interplay of NFATc1 and EZH2 in Pancreatic Cancer |
| title_short | Chromatin-Independent Interplay of NFATc1 and EZH2 in Pancreatic Cancer |
| title_sort | chromatin independent interplay of nfatc1 and ezh2 in pancreatic cancer |
| topic | chromatin EZH2 NFATc1 pancreatic cancer posttranslational EZH2 modification |
| url | https://www.mdpi.com/2073-4409/10/12/3463 |
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