Inhibition of EZH2 induces NK cell-mediated differentiation and death in invasive bladder cancer

Autores
Ramakrishnan, Swathi; Granger, Victoria; Rak, Monica; Hu, Qiang; Attwood, Kristopher; Aquila, Lanni; Krishnan, Nithya; Osiecki, Rafal; Azabdaftari, Gissou; Guru, Khurshid; Chatta, Gurkamal; Gueron, Geraldine; McNally, Lacey; Ohm, Joyce; Wang, Jianmin; Woloszynska-Read, Anna
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Lysine-specific demethylase 6A (KDM6A) and members of the Switch/Sucrose Non-Fermentable (SWI/SNF) family are known to counteract the activity of Enhancer of Zeste Homolog 2 (EZH2), which is often overexpressed and is associated with poor prognosis in muscle-invasive bladder cancer. Here we provide evidence that alterations in chromatin modifying enzymes, including KDM6A and members of the SWI/SNF complex, are frequent in muscle-invasive bladder cancer. We exploit the loss of function mutations in KDM6A and SWI/SNF complex to make bladder cancer cells susceptible to EZH2-based epigenetic therapy that activates an immune response to drive tumor cell differentiation and death. We reveal a novel mechanism of action of EZH2 inhibition, alone and in combination with cisplatin, which induces immune signaling with the largest changes observed in interferon gamma (IFN-γ). This upregulation is a result of activated natural killer (NK) signaling as demonstrated by the increase in NK cell-associated genes MIP-1α, ICAM1, ICAM2, and CD86 in xenografts treated with EZH2 inhibitors. Conversely, EZH2 inhibition results in decreased expression of pluripotency markers, ALDH2 and CK5, and increased cell death. Our results reveal a novel sensitivity of muscle-invasive bladder cancer cells with KMD6A and SWI/SNF mutations to EZH2 inhibition alone and in combination with cisplatin. This sensitivity is mediated through increased NK cell-related signaling resulting in tumor cell differentiation and cell death.
Fil: Ramakrishnan, Swathi. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Granger, Victoria. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Rak, Monica. Jagiellonian University; Polonia
Fil: Hu, Qiang. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Attwood, Kristopher. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Aquila, Lanni. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Krishnan, Nithya. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Osiecki, Rafal. Medical University Of Warsaw; Polonia
Fil: Azabdaftari, Gissou. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Guru, Khurshid. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Chatta, Gurkamal. Roswell Park Comprehensive Cancer Center; 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. Wake Forest Comprehensive Cancer Center; Estados Unidos
Fil: Ohm, Joyce. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Wang, Jianmin. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Woloszynska-Read, Anna. Roswell Park Comprehensive Cancer Center; Estados Unidos
Materia
EZ-H2
NATURAL KILLER
BLADDER
CANCER
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/123264
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/123264
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Inhibition of EZH2 induces NK cell-mediated differentiation and death in invasive bladder cancerRamakrishnan, SwathiGranger, VictoriaRak, MonicaHu, QiangAttwood, KristopherAquila, LanniKrishnan, NithyaOsiecki, RafalAzabdaftari, GissouGuru, KhurshidChatta, GurkamalGueron, GeraldineMcNally, LaceyOhm, JoyceWang, JianminWoloszynska-Read, AnnaEZ-H2NATURAL KILLERBLADDERCANCERhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Lysine-specific demethylase 6A (KDM6A) and members of the Switch/Sucrose Non-Fermentable (SWI/SNF) family are known to counteract the activity of Enhancer of Zeste Homolog 2 (EZH2), which is often overexpressed and is associated with poor prognosis in muscle-invasive bladder cancer. Here we provide evidence that alterations in chromatin modifying enzymes, including KDM6A and members of the SWI/SNF complex, are frequent in muscle-invasive bladder cancer. We exploit the loss of function mutations in KDM6A and SWI/SNF complex to make bladder cancer cells susceptible to EZH2-based epigenetic therapy that activates an immune response to drive tumor cell differentiation and death. We reveal a novel mechanism of action of EZH2 inhibition, alone and in combination with cisplatin, which induces immune signaling with the largest changes observed in interferon gamma (IFN-γ). This upregulation is a result of activated natural killer (NK) signaling as demonstrated by the increase in NK cell-associated genes MIP-1α, ICAM1, ICAM2, and CD86 in xenografts treated with EZH2 inhibitors. Conversely, EZH2 inhibition results in decreased expression of pluripotency markers, ALDH2 and CK5, and increased cell death. Our results reveal a novel sensitivity of muscle-invasive bladder cancer cells with KMD6A and SWI/SNF mutations to EZH2 inhibition alone and in combination with cisplatin. This sensitivity is mediated through increased NK cell-related signaling resulting in tumor cell differentiation and cell death.Fil: Ramakrishnan, Swathi. Roswell Park Comprehensive Cancer Center; Estados UnidosFil: Granger, Victoria. Roswell Park Comprehensive Cancer Center; Estados UnidosFil: Rak, Monica. Jagiellonian University; PoloniaFil: Hu, Qiang. Roswell Park Comprehensive Cancer Center; Estados UnidosFil: Attwood, Kristopher. Roswell Park Comprehensive Cancer Center; Estados UnidosFil: Aquila, Lanni. Roswell Park Comprehensive Cancer Center; Estados UnidosFil: Krishnan, Nithya. Roswell Park Comprehensive Cancer Center; Estados UnidosFil: Osiecki, Rafal. Medical University Of Warsaw; PoloniaFil: Azabdaftari, Gissou. Roswell Park Comprehensive Cancer Center; Estados UnidosFil: Guru, Khurshid. Roswell Park Comprehensive Cancer Center; Estados UnidosFil: Chatta, Gurkamal. Roswell Park Comprehensive Cancer Center; 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. Wake Forest Comprehensive Cancer Center; Estados UnidosFil: Ohm, Joyce. Roswell Park Comprehensive Cancer Center; Estados UnidosFil: Wang, Jianmin. Roswell Park Comprehensive Cancer Center; Estados UnidosFil: Woloszynska-Read, Anna. Roswell Park Comprehensive Cancer Center; Estados UnidosNature Publishing Group2019-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/123264Ramakrishnan, Swathi; Granger, Victoria; Rak, Monica; Hu, Qiang; Attwood, Kristopher; et al.; Inhibition of EZH2 induces NK cell-mediated differentiation and death in invasive bladder cancer; Nature Publishing Group; Cell Death and Differentiation; 26; 10; 1-2019; 2100-21141350-9047CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41418-019-0278-9info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:22:03Zoai:ri.conicet.gov.ar:11336/123264instacron: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:34982025-09-29 10:22:03.341CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Inhibition of EZH2 induces NK cell-mediated differentiation and death in invasive bladder cancer
title Inhibition of EZH2 induces NK cell-mediated differentiation and death in invasive bladder cancer
spellingShingle Inhibition of EZH2 induces NK cell-mediated differentiation and death in invasive bladder cancer
Ramakrishnan, Swathi
EZ-H2
NATURAL KILLER
BLADDER
CANCER
title_short Inhibition of EZH2 induces NK cell-mediated differentiation and death in invasive bladder cancer
title_full Inhibition of EZH2 induces NK cell-mediated differentiation and death in invasive bladder cancer
title_fullStr Inhibition of EZH2 induces NK cell-mediated differentiation and death in invasive bladder cancer
title_full_unstemmed Inhibition of EZH2 induces NK cell-mediated differentiation and death in invasive bladder cancer
title_sort Inhibition of EZH2 induces NK cell-mediated differentiation and death in invasive bladder cancer
dc.creator.none.fl_str_mv Ramakrishnan, Swathi
Granger, Victoria
Rak, Monica
Hu, Qiang
Attwood, Kristopher
Aquila, Lanni
Krishnan, Nithya
Osiecki, Rafal
Azabdaftari, Gissou
Guru, Khurshid
Chatta, Gurkamal
Gueron, Geraldine
McNally, Lacey
Ohm, Joyce
Wang, Jianmin
Woloszynska-Read, Anna
author Ramakrishnan, Swathi
author_facet Ramakrishnan, Swathi
Granger, Victoria
Rak, Monica
Hu, Qiang
Attwood, Kristopher
Aquila, Lanni
Krishnan, Nithya
Osiecki, Rafal
Azabdaftari, Gissou
Guru, Khurshid
Chatta, Gurkamal
Gueron, Geraldine
McNally, Lacey
Ohm, Joyce
Wang, Jianmin
Woloszynska-Read, Anna
author_role author
author2 Granger, Victoria
Rak, Monica
Hu, Qiang
Attwood, Kristopher
Aquila, Lanni
Krishnan, Nithya
Osiecki, Rafal
Azabdaftari, Gissou
Guru, Khurshid
Chatta, Gurkamal
Gueron, Geraldine
McNally, Lacey
Ohm, Joyce
Wang, Jianmin
Woloszynska-Read, Anna
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv EZ-H2
NATURAL KILLER
BLADDER
CANCER
topic EZ-H2
NATURAL KILLER
BLADDER
CANCER
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Lysine-specific demethylase 6A (KDM6A) and members of the Switch/Sucrose Non-Fermentable (SWI/SNF) family are known to counteract the activity of Enhancer of Zeste Homolog 2 (EZH2), which is often overexpressed and is associated with poor prognosis in muscle-invasive bladder cancer. Here we provide evidence that alterations in chromatin modifying enzymes, including KDM6A and members of the SWI/SNF complex, are frequent in muscle-invasive bladder cancer. We exploit the loss of function mutations in KDM6A and SWI/SNF complex to make bladder cancer cells susceptible to EZH2-based epigenetic therapy that activates an immune response to drive tumor cell differentiation and death. We reveal a novel mechanism of action of EZH2 inhibition, alone and in combination with cisplatin, which induces immune signaling with the largest changes observed in interferon gamma (IFN-γ). This upregulation is a result of activated natural killer (NK) signaling as demonstrated by the increase in NK cell-associated genes MIP-1α, ICAM1, ICAM2, and CD86 in xenografts treated with EZH2 inhibitors. Conversely, EZH2 inhibition results in decreased expression of pluripotency markers, ALDH2 and CK5, and increased cell death. Our results reveal a novel sensitivity of muscle-invasive bladder cancer cells with KMD6A and SWI/SNF mutations to EZH2 inhibition alone and in combination with cisplatin. This sensitivity is mediated through increased NK cell-related signaling resulting in tumor cell differentiation and cell death.
Fil: Ramakrishnan, Swathi. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Granger, Victoria. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Rak, Monica. Jagiellonian University; Polonia
Fil: Hu, Qiang. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Attwood, Kristopher. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Aquila, Lanni. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Krishnan, Nithya. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Osiecki, Rafal. Medical University Of Warsaw; Polonia
Fil: Azabdaftari, Gissou. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Guru, Khurshid. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Chatta, Gurkamal. Roswell Park Comprehensive Cancer Center; 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. Wake Forest Comprehensive Cancer Center; Estados Unidos
Fil: Ohm, Joyce. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Wang, Jianmin. Roswell Park Comprehensive Cancer Center; Estados Unidos
Fil: Woloszynska-Read, Anna. Roswell Park Comprehensive Cancer Center; Estados Unidos
description Lysine-specific demethylase 6A (KDM6A) and members of the Switch/Sucrose Non-Fermentable (SWI/SNF) family are known to counteract the activity of Enhancer of Zeste Homolog 2 (EZH2), which is often overexpressed and is associated with poor prognosis in muscle-invasive bladder cancer. Here we provide evidence that alterations in chromatin modifying enzymes, including KDM6A and members of the SWI/SNF complex, are frequent in muscle-invasive bladder cancer. We exploit the loss of function mutations in KDM6A and SWI/SNF complex to make bladder cancer cells susceptible to EZH2-based epigenetic therapy that activates an immune response to drive tumor cell differentiation and death. We reveal a novel mechanism of action of EZH2 inhibition, alone and in combination with cisplatin, which induces immune signaling with the largest changes observed in interferon gamma (IFN-γ). This upregulation is a result of activated natural killer (NK) signaling as demonstrated by the increase in NK cell-associated genes MIP-1α, ICAM1, ICAM2, and CD86 in xenografts treated with EZH2 inhibitors. Conversely, EZH2 inhibition results in decreased expression of pluripotency markers, ALDH2 and CK5, and increased cell death. Our results reveal a novel sensitivity of muscle-invasive bladder cancer cells with KMD6A and SWI/SNF mutations to EZH2 inhibition alone and in combination with cisplatin. This sensitivity is mediated through increased NK cell-related signaling resulting in tumor cell differentiation and cell death.
publishDate 2019
dc.date.none.fl_str_mv 2019-01
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/11336/123264
Ramakrishnan, Swathi; Granger, Victoria; Rak, Monica; Hu, Qiang; Attwood, Kristopher; et al.; Inhibition of EZH2 induces NK cell-mediated differentiation and death in invasive bladder cancer; Nature Publishing Group; Cell Death and Differentiation; 26; 10; 1-2019; 2100-2114
1350-9047
CONICET Digital
CONICET
url http://hdl.handle.net/11336/123264
identifier_str_mv Ramakrishnan, Swathi; Granger, Victoria; Rak, Monica; Hu, Qiang; Attwood, Kristopher; et al.; Inhibition of EZH2 induces NK cell-mediated differentiation and death in invasive bladder cancer; Nature Publishing Group; Cell Death and Differentiation; 26; 10; 1-2019; 2100-2114
1350-9047
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/s41418-019-0278-9
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/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
_version_ 1844614210784329728
score 13.070432

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