Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma
Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options and a poor prognosis. The critical role of epigenetic alterations such as changes in DNA methylation, histones modifications, and chromatin remodeling, in pancreatic tumors progre...
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2025-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-024-03268-5 |
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| author | Daniel Oyon Amaya Lopez-Pascual Borja Castello-Uribe Iker Uriarte Giulia Orsi Sofia Llorente Jasmin Elurbide Elena Adan-Villaescusa Emiliana Valbuena-Goiricelaya Ainara Irigaray-Miramon Maria Ujue Latasa Luz A. Martinez-Perez Luca Reggiani Bonetti Felipe Prosper Mariano Ponz-Sarvise Silvestre Vicent Antonio Pineda-Lucena David Ruiz-Clavijo Bruno Sangro Urko Aguirre Larracoechea Tian V. Tian Andrea Casadei-Gardini Irene Amat Maria Arechederra Carmen Berasain Jesus M. Urman Matias A. Avila Maite G. Fernandez-Barrena |
| author_facet | Daniel Oyon Amaya Lopez-Pascual Borja Castello-Uribe Iker Uriarte Giulia Orsi Sofia Llorente Jasmin Elurbide Elena Adan-Villaescusa Emiliana Valbuena-Goiricelaya Ainara Irigaray-Miramon Maria Ujue Latasa Luz A. Martinez-Perez Luca Reggiani Bonetti Felipe Prosper Mariano Ponz-Sarvise Silvestre Vicent Antonio Pineda-Lucena David Ruiz-Clavijo Bruno Sangro Urko Aguirre Larracoechea Tian V. Tian Andrea Casadei-Gardini Irene Amat Maria Arechederra Carmen Berasain Jesus M. Urman Matias A. Avila Maite G. Fernandez-Barrena |
| author_sort | Daniel Oyon |
| collection | DOAJ |
| description | Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options and a poor prognosis. The critical role of epigenetic alterations such as changes in DNA methylation, histones modifications, and chromatin remodeling, in pancreatic tumors progression is becoming increasingly recognized. Moreover, in PDAC these aberrant epigenetic mechanisms can also limit therapy efficacy. This study aimed to investigate the expression and prognostic significance of a key epigenetic complex encompassing DNA methyltransferase-1 (DNMT1), the histone methyltransferase G9a, and the scaffold protein UHRF1 in PDAC. We also evaluated the therapeutic potential of an innovative inhibitor targeting these epigenetic effectors. Methods Immunohistochemical analysis of DNMT1, G9a, and UHRF1 expression was conducted in human PDAC tissue samples. Staining was semi-quantitatively scored, and overexpression was defined as moderate to strong positivity. The prognostic impact was assessed by correlating protein expression with patient survival. The antitumoral effects of the dual DNMT1-G9a inhibitor CM272 were tested in PDAC cell lines, followed by transcriptomic analyses to identify underlying mechanisms. The in vivo antitumoral efficacy of CM272 was evaluated in PDAC xenograft and syngeneic mouse models, both alone and in combination with anti-PD1 immunotherapy. Results DNMT1, G9a, and UHRF1 were significantly overexpressed in PDAC cells and stroma compared to normal pancreatic tissues. Simultaneous overexpression of the three proteins was associated with significantly reduced survival in resected PDAC patients. CM272 exhibited potent antiproliferative activity in PDAC cell lines, inducing apoptosis and altering key metabolic and cell cycle-related genes. CM272 also enhanced chemotherapy sensitivity and significantly inhibited tumor growth in vivo without detectable toxicity. Combination of CM272 with anti-PD1 therapy further improved antitumor responses and immune cell infiltration, particularly CD4 + and CD8 + T cells. Conclusions The combined overexpression of DNMT1, G9a, and UHRF1 in PDAC is a strong predictor of poor prognosis. CM272, by targeting this epigenetic complex, shows promising therapeutic potential by inducing apoptosis, reprogramming metabolic pathways, and enhancing immune responses. The combination of CM272 with immunotherapy offers a novel, effective treatment strategy for PDAC. |
| format | Article |
| id | doaj-art-fd16fc4e2fe34d3f80704becfc24eddc |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-fd16fc4e2fe34d3f80704becfc24eddc2025-01-19T12:43:22ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-01-0144112110.1186/s13046-024-03268-5Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinomaDaniel Oyon0Amaya Lopez-Pascual1Borja Castello-Uribe2Iker Uriarte3Giulia Orsi4Sofia Llorente5Jasmin Elurbide6Elena Adan-Villaescusa7Emiliana Valbuena-Goiricelaya8Ainara Irigaray-Miramon9Maria Ujue Latasa10Luz A. Martinez-Perez11Luca Reggiani Bonetti12Felipe Prosper13Mariano Ponz-Sarvise14Silvestre Vicent15Antonio Pineda-Lucena16David Ruiz-Clavijo17Bruno Sangro18Urko Aguirre Larracoechea19Tian V. Tian20Andrea Casadei-Gardini21Irene Amat22Maria Arechederra23Carmen Berasain24Jesus M. Urman25Matias A. Avila26Maite G. Fernandez-Barrena27Department of Gastroenterology, Galdakao-Usansolo HospitalHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraOncology Department, University Hospital of ModenaPreclinical and Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO)Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraDepartment of Medical and Surgical Sciences for Children and Adults, Division of Pathology University-Hospital of Modena and Reggio EmiliaNavarra Institute for Health Research, IdiSNANavarra Institute for Health Research, IdiSNANavarra Institute for Health Research, IdiSNAMolecular Therapeutics Program, CIMA, CCUN, University of NavarraDepartment of Gastroenterology and Hepatology, Navarra University Hospital ComplexNavarra Institute for Health Research, IdiSNAResearch Unit, Osakidetza Basque Health Service, Barrualde-Galdakao Integrated Health Organisation, Galdakao-Usansolo HospitalPreclinical and Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO)Oncology Department, University Hospital of ModenaNavarra Institute for Health Research, IdiSNAHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraNavarra Institute for Health Research, IdiSNAHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraAbstract Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options and a poor prognosis. The critical role of epigenetic alterations such as changes in DNA methylation, histones modifications, and chromatin remodeling, in pancreatic tumors progression is becoming increasingly recognized. Moreover, in PDAC these aberrant epigenetic mechanisms can also limit therapy efficacy. This study aimed to investigate the expression and prognostic significance of a key epigenetic complex encompassing DNA methyltransferase-1 (DNMT1), the histone methyltransferase G9a, and the scaffold protein UHRF1 in PDAC. We also evaluated the therapeutic potential of an innovative inhibitor targeting these epigenetic effectors. Methods Immunohistochemical analysis of DNMT1, G9a, and UHRF1 expression was conducted in human PDAC tissue samples. Staining was semi-quantitatively scored, and overexpression was defined as moderate to strong positivity. The prognostic impact was assessed by correlating protein expression with patient survival. The antitumoral effects of the dual DNMT1-G9a inhibitor CM272 were tested in PDAC cell lines, followed by transcriptomic analyses to identify underlying mechanisms. The in vivo antitumoral efficacy of CM272 was evaluated in PDAC xenograft and syngeneic mouse models, both alone and in combination with anti-PD1 immunotherapy. Results DNMT1, G9a, and UHRF1 were significantly overexpressed in PDAC cells and stroma compared to normal pancreatic tissues. Simultaneous overexpression of the three proteins was associated with significantly reduced survival in resected PDAC patients. CM272 exhibited potent antiproliferative activity in PDAC cell lines, inducing apoptosis and altering key metabolic and cell cycle-related genes. CM272 also enhanced chemotherapy sensitivity and significantly inhibited tumor growth in vivo without detectable toxicity. Combination of CM272 with anti-PD1 therapy further improved antitumor responses and immune cell infiltration, particularly CD4 + and CD8 + T cells. Conclusions The combined overexpression of DNMT1, G9a, and UHRF1 in PDAC is a strong predictor of poor prognosis. CM272, by targeting this epigenetic complex, shows promising therapeutic potential by inducing apoptosis, reprogramming metabolic pathways, and enhancing immune responses. The combination of CM272 with immunotherapy offers a novel, effective treatment strategy for PDAC.https://doi.org/10.1186/s13046-024-03268-5Pancreatic ductal adenocarcinomaEpigenetic mechanismsDNMT1G9aUHRF1CM272 |
| spellingShingle | Daniel Oyon Amaya Lopez-Pascual Borja Castello-Uribe Iker Uriarte Giulia Orsi Sofia Llorente Jasmin Elurbide Elena Adan-Villaescusa Emiliana Valbuena-Goiricelaya Ainara Irigaray-Miramon Maria Ujue Latasa Luz A. Martinez-Perez Luca Reggiani Bonetti Felipe Prosper Mariano Ponz-Sarvise Silvestre Vicent Antonio Pineda-Lucena David Ruiz-Clavijo Bruno Sangro Urko Aguirre Larracoechea Tian V. Tian Andrea Casadei-Gardini Irene Amat Maria Arechederra Carmen Berasain Jesus M. Urman Matias A. Avila Maite G. Fernandez-Barrena Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma Journal of Experimental & Clinical Cancer Research Pancreatic ductal adenocarcinoma Epigenetic mechanisms DNMT1 G9a UHRF1 CM272 |
| title | Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma |
| title_full | Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma |
| title_fullStr | Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma |
| title_full_unstemmed | Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma |
| title_short | Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma |
| title_sort | targeting of the g9a dnmt1 and uhrf1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma |
| topic | Pancreatic ductal adenocarcinoma Epigenetic mechanisms DNMT1 G9a UHRF1 CM272 |
| url | https://doi.org/10.1186/s13046-024-03268-5 |
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