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

Autores
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, Geraldine; McNally, Lacey; Wang, Jianmin; Woloszynska-Read, Anna
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Ramakrishnan, Swathi. Roswell Park Cancer Institute; Estados Unidos
Fil: Hu, Qiang. Roswell Park Cancer Institute; Estados Unidos
Fil: Krishnan, Nithya. Roswell Park Cancer Institute; Estados Unidos
Fil: Wang, Dan. Roswell Park Cancer Institute; Estados Unidos
Fil: Smit, Evelyn. Roswell Park Cancer Institute; Estados Unidos
Fil: Granger, Victoria. Roswell Park Cancer Institute; Estados Unidos
Fil: Rak, Monika. Jagiellonian University; Polonia
Fil: Attwood, Kristopher. Roswell Park Cancer Institute; Estados Unidos
Fil: Johnson, Candace. Roswell Park Cancer Institute; Estados Unidos
Fil: Morrison, Carl. Roswell Park Cancer Institute; Estados Unidos
Fil: Pili, Roberto. Indiana University; Estados Unidos
Fil: Chatta, Gurkamal. Roswell Park Cancer Institute; Estados Unidos
Fil: Guru, Khurshid. Roswell Park Cancer Institute; Estados Unidos
Fil: Gueron, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: McNally, Lacey. University of Louisville; Estados Unidos
Fil: Wang, Jianmin. Roswell Park Cancer Institute; Estados Unidos
Fil: Woloszynska-Read, Anna. Roswell Park Cancer Institute; Estados Unidos
Materia
decitabine
DNA methylation
NOTCH1
cancer
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/53915
Acceder
id CONICETDig_b2cb3bd941b222825ee342790c56d532
oai_identifier_str oai:ri.conicet.gov.ar:11336/53915
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancerRamakrishnan, SwathiHu, QiangKrishnan, NithyaWang, DanSmit, EvelynGranger, VictoriaRak, MonikaAttwood, KristopherJohnson, CandaceMorrison, CarlPili, RobertoChatta, GurkamalGuru, KhurshidGueron, GeraldineMcNally, LaceyWang, JianminWoloszynska-Read, AnnadecitabineDNA methylationNOTCH1cancerhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Aberrant 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.Fil: Ramakrishnan, Swathi. Roswell Park Cancer Institute; Estados UnidosFil: Hu, Qiang. Roswell Park Cancer Institute; Estados UnidosFil: Krishnan, Nithya. Roswell Park Cancer Institute; Estados UnidosFil: Wang, Dan. Roswell Park Cancer Institute; Estados UnidosFil: Smit, Evelyn. Roswell Park Cancer Institute; Estados UnidosFil: Granger, Victoria. Roswell Park Cancer Institute; Estados UnidosFil: Rak, Monika. Jagiellonian University; PoloniaFil: Attwood, Kristopher. Roswell Park Cancer Institute; Estados UnidosFil: Johnson, Candace. Roswell Park Cancer Institute; Estados UnidosFil: Morrison, Carl. Roswell Park Cancer Institute; Estados UnidosFil: Pili, Roberto. Indiana University; Estados UnidosFil: Chatta, Gurkamal. Roswell Park Cancer Institute; Estados UnidosFil: Guru, Khurshid. Roswell Park Cancer Institute; Estados UnidosFil: Gueron, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: McNally, Lacey. University of Louisville; Estados UnidosFil: Wang, Jianmin. Roswell Park Cancer Institute; Estados UnidosFil: Woloszynska-Read, Anna. Roswell Park Cancer Institute; Estados UnidosNature Publishing Group2017-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/53915Ramakrishnan, 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; 1-132041-4889CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41419-017-0024-5info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41419-017-0024-5info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-17T10:41:23Zoai:ri.conicet.gov.ar:11336/53915instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-17 10:41:23.705CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer
title Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer
spellingShingle Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer
Ramakrishnan, Swathi
decitabine
DNA methylation
NOTCH1
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
dc.creator.none.fl_str_mv 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, Geraldine
McNally, Lacey
Wang, Jianmin
Woloszynska-Read, Anna
author Ramakrishnan, Swathi
author_facet 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, Geraldine
McNally, Lacey
Wang, Jianmin
Woloszynska-Read, Anna
author_role author
author2 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, Geraldine
McNally, Lacey
Wang, Jianmin
Woloszynska-Read, Anna
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv decitabine
DNA methylation
NOTCH1
cancer
topic decitabine
DNA methylation
NOTCH1
cancer
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Ramakrishnan, Swathi. Roswell Park Cancer Institute; Estados Unidos
Fil: Hu, Qiang. Roswell Park Cancer Institute; Estados Unidos
Fil: Krishnan, Nithya. Roswell Park Cancer Institute; Estados Unidos
Fil: Wang, Dan. Roswell Park Cancer Institute; Estados Unidos
Fil: Smit, Evelyn. Roswell Park Cancer Institute; Estados Unidos
Fil: Granger, Victoria. Roswell Park Cancer Institute; Estados Unidos
Fil: Rak, Monika. Jagiellonian University; Polonia
Fil: Attwood, Kristopher. Roswell Park Cancer Institute; Estados Unidos
Fil: Johnson, Candace. Roswell Park Cancer Institute; Estados Unidos
Fil: Morrison, Carl. Roswell Park Cancer Institute; Estados Unidos
Fil: Pili, Roberto. Indiana University; Estados Unidos
Fil: Chatta, Gurkamal. Roswell Park Cancer Institute; Estados Unidos
Fil: Guru, Khurshid. Roswell Park Cancer Institute; Estados Unidos
Fil: Gueron, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: McNally, Lacey. University of Louisville; Estados Unidos
Fil: Wang, Jianmin. Roswell Park Cancer Institute; Estados Unidos
Fil: Woloszynska-Read, Anna. Roswell Park Cancer Institute; Estados Unidos
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.
publishDate 2017
dc.date.none.fl_str_mv 2017-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/53915
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
2041-4889
CONICET Digital
CONICET
url http://hdl.handle.net/11336/53915
identifier_str_mv 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
2041-4889
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/s41419-017-0024-5
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41419-017-0024-5
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.001348

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