Artículo

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" (2017) Cell Death and Disease. 8(12)
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Abstract:

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).

Registro:

Documento: Artículo
Título:Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer
Autor: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.
Filiación:Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, United States
Department of Bioinformatics and BioStatistics, Roswell Park Cancer Institute, Buffalo, NY 14263, United States
Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, 31-007, Poland
Department of Medicine, Indiana University, Bloomington, IN 47405, United States
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, United States
Department of Biological Chemistry, School of Sciences, University of Buenos Aires, IQUIBICEN-CONICET Argentina, Intendente Guiraldes 2160, CABA, Buenos Aires, 1428, Argentina
Department of Medicine, University of Louisville, Louisville, KY 40292, United States
Palabras clave: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
Año:2017
Volumen:8
Número:12
DOI: http://dx.doi.org/10.1038/s41419-017-0024-5
Título revista:Cell Death and Disease
Título revista abreviado:Cell Death Dis.
ISSN:20414889
CAS:beta galactosidase; decitabine, 2353-33-5; azacitidine, 320-67-2, 52934-49-3; Antibodies, Monoclonal; Antimetabolites, Antineoplastic; Azacitidine; beta-Galactosidase; Cyclin-Dependent Kinase Inhibitor p16; decitabine; IL6 protein, human; Interleukin-6; Keratin-5; NOTCH1 protein, human; P16 protein, human; Receptor, Notch1
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_20414889_v8_n12_p_Ramakrishnan

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Citas:

---------- APA ----------
Ramakrishnan, S., Hu, Q., Krishnan, N., Wang, D., Smit, E., Granger, V., Rak, M.,..., Woloszynska-Read, A. (2017) . Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer. Cell Death and Disease, 8(12).
http://dx.doi.org/10.1038/s41419-017-0024-5
---------- CHICAGO ----------
Ramakrishnan, S., Hu, Q., Krishnan, N., Wang, D., Smit, E., Granger, V., et al. "Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer" . Cell Death and Disease 8, no. 12 (2017).
http://dx.doi.org/10.1038/s41419-017-0024-5
---------- MLA ----------
Ramakrishnan, S., Hu, Q., Krishnan, N., Wang, D., Smit, E., Granger, V., et al. "Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer" . Cell Death and Disease, vol. 8, no. 12, 2017.
http://dx.doi.org/10.1038/s41419-017-0024-5
---------- VANCOUVER ----------
Ramakrishnan, S., Hu, Q., Krishnan, N., Wang, D., Smit, E., Granger, V., et al. Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer. Cell Death Dis. 2017;8(12).
http://dx.doi.org/10.1038/s41419-017-0024-5