Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer
Aberrant DNA methylation observed in cancer can provide survival benefits to cells by silencing genes essential for anti-tumor activity. DNA-demethylating agents such as Decitabine (DAC)/Azacitidine (AZA) activate otherwise silenced tumor suppressor genes, alter immune response and epigenetically re...
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| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_20414889_v8_n12_p_Ramakrishnan |
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todo:paper_20414889_v8_n12_p_Ramakrishnan2023-10-03T16:37:56Z Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer Ramakrishnan, S. Hu, Q. Krishnan, N. Wang, D. Smit, E. Granger, V. Rak, M. Attwood, K. Johnson, C. Morrison, C. Pili, R. Chatta, G. Guru, K. Gueron, G. McNally, L. Wang, J. Woloszynska-Read, A. beta galactosidase decitabine double stranded RNA interleukin 6 messenger RNA Notch1 receptor protein p16 transcriptome antineoplastic antimetabolite azacitidine beta galactosidase cyclin dependent kinase inhibitor 2A cytokeratin 5 decitabine IL6 protein, human interleukin 6 monoclonal antibody NOTCH1 protein, human Notch1 receptor P16 protein, human Article cancer patient cell proliferation cell size cell structure controlled study cytokine release disease marker DNA methylation drug blood level gene overexpression HT-1376 cell line human human cell MDA-MB-231/B02 cell line muscle invasive bladder cancer priority journal T24 cell line transcriptomics analogs and derivatives antagonists and inhibitors bladder tumor gene expression regulation genetic epigenesis genetics immunology metabolism pathology signal transduction smooth muscle treatment outcome tumor cell line tumor invasion Antibodies, Monoclonal Antimetabolites, Antineoplastic Azacitidine beta-Galactosidase Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p16 Epigenesis, Genetic Gene Expression Regulation, Neoplastic Humans Interleukin-6 Keratin-5 Muscle, Smooth Neoplasm Invasiveness Receptor, Notch1 Signal Transduction Treatment Outcome Urinary Bladder Neoplasms Aberrant DNA methylation observed in cancer can provide survival benefits to cells by silencing genes essential for anti-tumor activity. DNA-demethylating agents such as Decitabine (DAC)/Azacitidine (AZA) activate otherwise silenced tumor suppressor genes, alter immune response and epigenetically reprogram tumor cells. In this study, we show that non-cytotoxic nanomolar DAC concentrations modify the bladder cancer transcriptome to activate NOTCH1 at the mRNA and protein level, increase double-stranded RNA sensors and CK5-dependent differentiation. Importantly, DAC treatment increases ICN1 expression (the active intracellular domain of NOTCH1) significantly inhibiting cell proliferation and causing changes in cell size inducing morphological alterations reminiscent of senescence. These changes were not associated with β-galactosidase activity or increased p16 levels, but instead were associated with substantial IL-6 release. Increased IL-6 release was observed in both DAC-treated and ICN1 overexpressing cells as compared to control cells. Exogenous IL-6 expression was associated with a similar enlarged cell morphology that was rescued by the addition of a monoclonal antibody against IL-6. Treatment with DAC, overexpression with ICN1 or addition of exogenous IL-6 showed CK5 reduction, a surrogate marker of differentiation. Overall this study suggests that in MIBC cells, DNA hypomethylation increases NOTCH1 expression and IL-6 release to induce CK5-related differentiation. © 2017 The Author(s). JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_20414889_v8_n12_p_Ramakrishnan |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
beta galactosidase decitabine double stranded RNA interleukin 6 messenger RNA Notch1 receptor protein p16 transcriptome antineoplastic antimetabolite azacitidine beta galactosidase cyclin dependent kinase inhibitor 2A cytokeratin 5 decitabine IL6 protein, human interleukin 6 monoclonal antibody NOTCH1 protein, human Notch1 receptor P16 protein, human Article cancer patient cell proliferation cell size cell structure controlled study cytokine release disease marker DNA methylation drug blood level gene overexpression HT-1376 cell line human human cell MDA-MB-231/B02 cell line muscle invasive bladder cancer priority journal T24 cell line transcriptomics analogs and derivatives antagonists and inhibitors bladder tumor gene expression regulation genetic epigenesis genetics immunology metabolism pathology signal transduction smooth muscle treatment outcome tumor cell line tumor invasion Antibodies, Monoclonal Antimetabolites, Antineoplastic Azacitidine beta-Galactosidase Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p16 Epigenesis, Genetic Gene Expression Regulation, Neoplastic Humans Interleukin-6 Keratin-5 Muscle, Smooth Neoplasm Invasiveness Receptor, Notch1 Signal Transduction Treatment Outcome Urinary Bladder Neoplasms |
| spellingShingle |
beta galactosidase decitabine double stranded RNA interleukin 6 messenger RNA Notch1 receptor protein p16 transcriptome antineoplastic antimetabolite azacitidine beta galactosidase cyclin dependent kinase inhibitor 2A cytokeratin 5 decitabine IL6 protein, human interleukin 6 monoclonal antibody NOTCH1 protein, human Notch1 receptor P16 protein, human Article cancer patient cell proliferation cell size cell structure controlled study cytokine release disease marker DNA methylation drug blood level gene overexpression HT-1376 cell line human human cell MDA-MB-231/B02 cell line muscle invasive bladder cancer priority journal T24 cell line transcriptomics analogs and derivatives antagonists and inhibitors bladder tumor gene expression regulation genetic epigenesis genetics immunology metabolism pathology signal transduction smooth muscle treatment outcome tumor cell line tumor invasion Antibodies, Monoclonal Antimetabolites, Antineoplastic Azacitidine beta-Galactosidase Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p16 Epigenesis, Genetic Gene Expression Regulation, Neoplastic Humans Interleukin-6 Keratin-5 Muscle, Smooth Neoplasm Invasiveness Receptor, Notch1 Signal Transduction Treatment Outcome Urinary Bladder Neoplasms Ramakrishnan, S. Hu, Q. Krishnan, N. Wang, D. Smit, E. Granger, V. Rak, M. Attwood, K. Johnson, C. Morrison, C. Pili, R. Chatta, G. Guru, K. Gueron, G. McNally, L. Wang, J. Woloszynska-Read, A. Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer |
| topic_facet |
beta galactosidase decitabine double stranded RNA interleukin 6 messenger RNA Notch1 receptor protein p16 transcriptome antineoplastic antimetabolite azacitidine beta galactosidase cyclin dependent kinase inhibitor 2A cytokeratin 5 decitabine IL6 protein, human interleukin 6 monoclonal antibody NOTCH1 protein, human Notch1 receptor P16 protein, human Article cancer patient cell proliferation cell size cell structure controlled study cytokine release disease marker DNA methylation drug blood level gene overexpression HT-1376 cell line human human cell MDA-MB-231/B02 cell line muscle invasive bladder cancer priority journal T24 cell line transcriptomics analogs and derivatives antagonists and inhibitors bladder tumor gene expression regulation genetic epigenesis genetics immunology metabolism pathology signal transduction smooth muscle treatment outcome tumor cell line tumor invasion Antibodies, Monoclonal Antimetabolites, Antineoplastic Azacitidine beta-Galactosidase Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p16 Epigenesis, Genetic Gene Expression Regulation, Neoplastic Humans Interleukin-6 Keratin-5 Muscle, Smooth Neoplasm Invasiveness Receptor, Notch1 Signal Transduction Treatment Outcome Urinary Bladder Neoplasms |
| description |
Aberrant DNA methylation observed in cancer can provide survival benefits to cells by silencing genes essential for anti-tumor activity. DNA-demethylating agents such as Decitabine (DAC)/Azacitidine (AZA) activate otherwise silenced tumor suppressor genes, alter immune response and epigenetically reprogram tumor cells. In this study, we show that non-cytotoxic nanomolar DAC concentrations modify the bladder cancer transcriptome to activate NOTCH1 at the mRNA and protein level, increase double-stranded RNA sensors and CK5-dependent differentiation. Importantly, DAC treatment increases ICN1 expression (the active intracellular domain of NOTCH1) significantly inhibiting cell proliferation and causing changes in cell size inducing morphological alterations reminiscent of senescence. These changes were not associated with β-galactosidase activity or increased p16 levels, but instead were associated with substantial IL-6 release. Increased IL-6 release was observed in both DAC-treated and ICN1 overexpressing cells as compared to control cells. Exogenous IL-6 expression was associated with a similar enlarged cell morphology that was rescued by the addition of a monoclonal antibody against IL-6. Treatment with DAC, overexpression with ICN1 or addition of exogenous IL-6 showed CK5 reduction, a surrogate marker of differentiation. Overall this study suggests that in MIBC cells, DNA hypomethylation increases NOTCH1 expression and IL-6 release to induce CK5-related differentiation. © 2017 The Author(s). |
| format |
JOUR |
| author |
Ramakrishnan, S. Hu, Q. Krishnan, N. Wang, D. Smit, E. Granger, V. Rak, M. Attwood, K. Johnson, C. Morrison, C. Pili, R. Chatta, G. Guru, K. Gueron, G. McNally, L. Wang, J. Woloszynska-Read, A. |
| author_facet |
Ramakrishnan, S. Hu, Q. Krishnan, N. Wang, D. Smit, E. Granger, V. Rak, M. Attwood, K. Johnson, C. Morrison, C. Pili, R. Chatta, G. Guru, K. Gueron, G. McNally, L. Wang, J. Woloszynska-Read, A. |
| author_sort |
Ramakrishnan, S. |
| title |
Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer |
| title_short |
Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer |
| title_full |
Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer |
| title_fullStr |
Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer |
| title_full_unstemmed |
Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer |
| title_sort |
decitabine, a dna-demethylating agent, promotes differentiation via notch1 signaling and alters immune-related pathways in muscle-invasive bladder cancer |
| url |
http://hdl.handle.net/20.500.12110/paper_20414889_v8_n12_p_Ramakrishnan |
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