G9a/DNMT1 co-targeting inhibits non-small cell lung cancer growth and reprograms tumor cells to respond to cancer-drugs through SCARA5 and AOX1.
Por:
Exposito F, Redrado M, Serrano D, Calabuig-Fariñas S, Bao-Caamano A, Gallach S, Jantus-Lewintre E, Diaz-Lagares A, Rodriguez-Casanova A, Sandoval J, San Jose-Eneriz E, Garcia J, Redin E, Senent Y, Leon S, Pio R, Lopez R, Oyarzabal J, Pineda-Lucena A, Agirre X, Montuenga LM, Prosper F and Calvo A
Publicada:
2 nov 2024
Resumen:
The treatment of non-small cell lung cancer (NSCLC) patients has significantly improved with recent therapeutic strategies; however, many patients still do not benefit from them. As a result, new treatment approaches are urgently needed. In this study, we evaluated the antitumor efficacy of co-targeting G9a and DNMT1 enzymes and its potential as a cancer drug sensitizer. We observed co-expression and overexpression of G9a and DNMT1 in NSCLC, which were associated with poor prognosis. Co-targeting G9a/DNMT1 with the drug CM-272 reduced proliferation and induced cell death in a panel of human and murine NSCLC cell lines. Additionally, the transcriptomes of these cells were reprogrammed to become highly responsive to chemotherapy (cisplatin), targeted therapy (trametinib), and epigenetic therapy (vorinostat). In vivo, CM-272 reduced tumor volume in human and murine cell-derived cancer models, and this effect was synergistically enhanced by cisplatin. The expression of SCARA5 and AOX1 was induced by CM-272, and both proteins were found to be essential for the antiproliferative response, as gene silencing decreased cytotoxicity. Furthermore, the expression of SCARA5 and AOX1 was positively correlated with each other and inversely correlated with G9a and DNMT1 expression in NSCLC patients. SCARA5 and AOX1 DNA promoters were hypermethylated in NSCLC, and SCARA5 methylation was identified as an epigenetic biomarker in tumors and liquid biopsies from NSCLC patients. Thus, we demonstrate that co-targeting G9a/DNMT1 is a promising strategy to enhance the efficacy of cancer drugs, and SCARA5 methylation could serve as a non-invasive biomarker to monitor tumor progression.
Filiaciones:
Exposito F:
Program in Solid Tumors, Cima-Universidad de Navarra, Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
CIBERONC, ISCIII, Madrid, Spain
IDISNA, Pamplona, Spain
Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
Yale Cancer Center, New Haven, CT, USA
Redrado M:
Program in Solid Tumors, Cima-Universidad de Navarra, Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
IDISNA, Pamplona, Spain
Serrano D:
Program in Solid Tumors, Cima-Universidad de Navarra, Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
CIBERONC, ISCIII, Madrid, Spain
IDISNA, Pamplona, Spain
Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
:
CIBERONC, ISCIII, Madrid, Spain
Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, 46014, Valencia, Spain
TRIAL Mixed Unit, Centro de Investigación Príncipe Felipe-Fundación para la Investigación del Hospital General Universitario de Valencia, 46014, Valencia, Spain
Department of Pathology, Universitat de València, 46010, Valencia, Spain
Bao-Caamano A:
Epigenomics Units, Cancer Epigenomics, Translational Medical Oncology Group (ONCOGAL), Health Research Institute of Santiago de Compostela (IDIS), and Department of Clinical Analysis, University Hospital Complex of Santiago de Compostela (CHUS), Roche-CHUS Joint Unit (ONCOMET), Health Research Institute of Santiago (IDIS), 15706, Santiago de Compostela, Spain, 15706, Santiago de Compostela, Spain
Gallach S:
CIBERONC, ISCIII, Madrid, Spain
Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, 46014, Valencia, Spain
TRIAL Mixed Unit, Centro de Investigación Príncipe Felipe-Fundación para la Investigación del Hospital General Universitario de Valencia, 46014, Valencia, Spain
:
CIBERONC, ISCIII, Madrid, Spain
Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, 46014, Valencia, Spain
TRIAL Mixed Unit, Centro de Investigación Príncipe Felipe-Fundación para la Investigación del Hospital General Universitario de Valencia, 46014, Valencia, Spain
Department of Biotechnology, Universitat Politècnica de València, 46022, Valencia, Spain
Diaz-Lagares A:
CIBERONC, ISCIII, Madrid, Spain
Epigenomics Units, Cancer Epigenomics, Translational Medical Oncology Group (ONCOGAL), Health Research Institute of Santiago de Compostela (IDIS), and Department of Clinical Analysis, University Hospital Complex of Santiago de Compostela (CHUS), Roche-CHUS Joint Unit (ONCOMET), Health Research Institute of Santiago (IDIS), 15706, Santiago de Compostela, Spain, 15706, Santiago de Compostela, Spain
Rodriguez-Casanova A:
Epigenomics Units, Cancer Epigenomics, Translational Medical Oncology Group (ONCOGAL), Health Research Institute of Santiago de Compostela (IDIS), and Department of Clinical Analysis, University Hospital Complex of Santiago de Compostela (CHUS), Roche-CHUS Joint Unit (ONCOMET), Health Research Institute of Santiago (IDIS), 15706, Santiago de Compostela, Spain, 15706, Santiago de Compostela, Spain
Sandoval J:
Biomarkers and Precision Medicine (UBMP) and Epigenomics Unit, IIS, La Fe, 46026, Valencia, Spain
San Jose-Eneriz E:
CIBERONC, ISCIII, Madrid, Spain
IDISNA, Pamplona, Spain
Division of Hemato-Oncology, Cima-Universidad de Navarra, Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
Garcia J:
Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
Redin E:
Program in Solid Tumors, Cima-Universidad de Navarra, Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
CIBERONC, ISCIII, Madrid, Spain
IDISNA, Pamplona, Spain
Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
Senent Y:
Program in Solid Tumors, Cima-Universidad de Navarra, Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
Leon S:
Program in Solid Tumors, Cima-Universidad de Navarra, Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
CIBERONC, ISCIII, Madrid, Spain
Pio R:
Program in Solid Tumors, Cima-Universidad de Navarra, Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
CIBERONC, ISCIII, Madrid, Spain
Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
Lopez R:
CIBERONC, ISCIII, Madrid, Spain
Epigenomics Units, Cancer Epigenomics, Translational Medical Oncology Group (ONCOGAL), Health Research Institute of Santiago de Compostela (IDIS), and Department of Clinical Analysis, University Hospital Complex of Santiago de Compostela (CHUS), Roche-CHUS Joint Unit (ONCOMET), Health Research Institute of Santiago (IDIS), 15706, Santiago de Compostela, Spain, 15706, Santiago de Compostela, Spain
Oyarzabal J:
Molecular Therapeutics Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
:
Molecular Therapeutics Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
Agirre X:
CIBERONC, ISCIII, Madrid, Spain
IDISNA, Pamplona, Spain
Division of Hemato-Oncology, Cima-Universidad de Navarra, Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
Montuenga LM:
Program in Solid Tumors, Cima-Universidad de Navarra, Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
CIBERONC, ISCIII, Madrid, Spain
IDISNA, Pamplona, Spain
Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
Prosper F:
CIBERONC, ISCIII, Madrid, Spain
IDISNA, Pamplona, Spain
Hematology and Cell Therapy Service, Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
Calvo A:
Program in Solid Tumors, Cima-Universidad de Navarra, Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain.
CIBERONC, ISCIII, Madrid, Spain.
IDISNA, Pamplona, Spain.
Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain.
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