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Artículo

Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer

Ramakrishnan, Swathi; Hu, Qiang; Krishnan, Nithya; Wang, Dan; Smit, Evelyn; Granger, Victoria; Rak, Monika; Attwood, Kristopher; Johnson, Candace; Morrison, Carl; Pili, Roberto; Chatta, Gurkamal; Guru, Khurshid; Gueron, GeraldineIcon ; McNally, Lacey; Wang, Jianmin; Woloszynska-Read, Anna
Fecha de publicación: 12/2017
Editorial: Nature Publishing Group
Revista: Cell Death & Disease
ISSN: 2041-4889
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Inmunología

Resumen

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.
Palabras clave: Decitabine , Dna Methylation , Notch1 , Cancer
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/53915
DOI: https://dx.doi.org/10.1038/s41419-017-0024-5
URL: https://www.nature.com/articles/s41419-017-0024-5
Colecciones
Articulos(IQUIBICEN)
Articulos de INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CS. EXACTAS Y NATURALES
Citación
Ramakrishnan, Swathi; Hu, Qiang; Krishnan, Nithya; Wang, Dan; Smit, Evelyn; et al.; Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer; Nature Publishing Group; Cell Death & Disease; 8; 12; 12-2017; 1-13
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