Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axis

Autores
Wu, Meng; Ingram, Lishann; Tolosa, Ezequiel Julian; Vera, Renzo Emanuel; Li, Qianjin; Kim, Sungjin; Ma, Yongjie; Spyropoulos, Demetri D.; Beharry, Zanna; Huang, Jiaoti; Fernandez Zapico, Martin Ernesto; Cai, Houjian
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Although the differentiation of oncogenically transformed basal progenitor cells is one of the key steps in prostate tumorigenesis, the mechanisms mediating this cellular process are still largely unknown. Here we demonstrate that an expanded p63+ and CK5+ basal/progenitor cell population, induced by the concomitant activation of oncogenic Kras(G12D) and androgen receptor (AR) signaling, underwent cell differentiation in vivo. The differentiation process led to suppression of p63-expressing cells with a decreased number of CK5+ basal cells but an increase of CK8+ luminal tumorigenic cells and revealed a hierarchal lineage pattern consisting of p63+/CK5+ progenitor, CK5+/CK8+ transitional progenitor, and CK8+ differentiated luminal cells. Further analysis of the phenotype showed that Kras-AR axis-induced tumorigenesis was mediated by Gli transcription factors. Combined blocking of the activators of this family of proteins (Gli1 and Gli2) inhibited the proliferation of p63+ and CK5+ basal/progenitor cells and development of tumors. Finally, we identified that Gli1 and Gli2 exhibited different functions in the regulation of p63 expression or proliferation of p63+ cells in Kras-AR driven tumors. Gli2, but not Gli1, transcriptionally regulated the expression levels of p63 and prostate sphere formation. Our study provides evidence of a novel mechanism mediating pathological dysregulation of basal/progenitor cells through the differential activation of the Gli transcription factors. Also, these findings define Gli proteins as new downstream mediators of the Kras-AR axis in prostate carcinogenesis and open a potential therapeutic avenue of targeting prostate cancer progression by inhibiting Gli signaling.
Fil: Wu, Meng. University of Georgia; Grecia
Fil: Ingram, Lishann. University of Georgia; Grecia
Fil: Tolosa, Ezequiel Julian. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Mayo Clinic; Estados Unidos
Fil: Vera, Renzo Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Mayo Clinic; Estados Unidos
Fil: Li, Qianjin. University of Georgia; Grecia
Fil: Kim, Sungjin. University of Georgia; Grecia
Fil: Ma, Yongjie. University of Georgia; Grecia
Fil: Spyropoulos, Demetri D.. Medical University of South Carolina; Estados Unidos
Fil: Beharry, Zanna. Florida Gulf Coast University; Estados Unidos
Fil: Huang, Jiaoti. University of Duke; Estados Unidos
Fil: Fernandez Zapico, Martin Ernesto. Mayo Clinic; Estados Unidos
Fil: Cai, Houjian. University of Georgia; Grecia
Materia
GTPase Kras (KRAS)
Hedgehog signaling pathway
androgen receptor
p63
prostate 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:11336/61772
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/61772
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axisWu, MengIngram, LishannTolosa, Ezequiel JulianVera, Renzo EmanuelLi, QianjinKim, SungjinMa, YongjieSpyropoulos, Demetri D.Beharry, ZannaHuang, JiaotiFernandez Zapico, Martin ErnestoCai, HoujianGTPase Kras (KRAS)Hedgehog signaling pathwayandrogen receptorp63prostate cancerhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Although the differentiation of oncogenically transformed basal progenitor cells is one of the key steps in prostate tumorigenesis, the mechanisms mediating this cellular process are still largely unknown. Here we demonstrate that an expanded p63+ and CK5+ basal/progenitor cell population, induced by the concomitant activation of oncogenic Kras(G12D) and androgen receptor (AR) signaling, underwent cell differentiation in vivo. The differentiation process led to suppression of p63-expressing cells with a decreased number of CK5+ basal cells but an increase of CK8+ luminal tumorigenic cells and revealed a hierarchal lineage pattern consisting of p63+/CK5+ progenitor, CK5+/CK8+ transitional progenitor, and CK8+ differentiated luminal cells. Further analysis of the phenotype showed that Kras-AR axis-induced tumorigenesis was mediated by Gli transcription factors. Combined blocking of the activators of this family of proteins (Gli1 and Gli2) inhibited the proliferation of p63+ and CK5+ basal/progenitor cells and development of tumors. Finally, we identified that Gli1 and Gli2 exhibited different functions in the regulation of p63 expression or proliferation of p63+ cells in Kras-AR driven tumors. Gli2, but not Gli1, transcriptionally regulated the expression levels of p63 and prostate sphere formation. Our study provides evidence of a novel mechanism mediating pathological dysregulation of basal/progenitor cells through the differential activation of the Gli transcription factors. Also, these findings define Gli proteins as new downstream mediators of the Kras-AR axis in prostate carcinogenesis and open a potential therapeutic avenue of targeting prostate cancer progression by inhibiting Gli signaling.Fil: Wu, Meng. University of Georgia; GreciaFil: Ingram, Lishann. University of Georgia; GreciaFil: Tolosa, Ezequiel Julian. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Mayo Clinic; Estados UnidosFil: Vera, Renzo Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Mayo Clinic; Estados UnidosFil: Li, Qianjin. University of Georgia; GreciaFil: Kim, Sungjin. University of Georgia; GreciaFil: Ma, Yongjie. University of Georgia; GreciaFil: Spyropoulos, Demetri D.. Medical University of South Carolina; Estados UnidosFil: Beharry, Zanna. Florida Gulf Coast University; Estados UnidosFil: Huang, Jiaoti. University of Duke; Estados UnidosFil: Fernandez Zapico, Martin Ernesto. Mayo Clinic; Estados UnidosFil: Cai, Houjian. University of Georgia; GreciaAmerican Society for Biochemistry and Molecular Biology2016-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/61772Wu, Meng; Ingram, Lishann; Tolosa, Ezequiel Julian; Vera, Renzo Emanuel; Li, Qianjin; et al.; Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axis; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 291; 49; 12-2016; 25749-257600021-9258CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M116.753129info:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/content/291/49/25749info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:12:08Zoai:ri.conicet.gov.ar:11336/61772instacron: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:34982025-09-03 10:12:09.081CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axis
title Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axis
spellingShingle Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axis
Wu, Meng
GTPase Kras (KRAS)
Hedgehog signaling pathway
androgen receptor
p63
prostate cancer
title_short Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axis
title_full Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axis
title_fullStr Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axis
title_full_unstemmed Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axis
title_sort Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axis
dc.creator.none.fl_str_mv Wu, Meng
Ingram, Lishann
Tolosa, Ezequiel Julian
Vera, Renzo Emanuel
Li, Qianjin
Kim, Sungjin
Ma, Yongjie
Spyropoulos, Demetri D.
Beharry, Zanna
Huang, Jiaoti
Fernandez Zapico, Martin Ernesto
Cai, Houjian
author Wu, Meng
author_facet Wu, Meng
Ingram, Lishann
Tolosa, Ezequiel Julian
Vera, Renzo Emanuel
Li, Qianjin
Kim, Sungjin
Ma, Yongjie
Spyropoulos, Demetri D.
Beharry, Zanna
Huang, Jiaoti
Fernandez Zapico, Martin Ernesto
Cai, Houjian
author_role author
author2 Ingram, Lishann
Tolosa, Ezequiel Julian
Vera, Renzo Emanuel
Li, Qianjin
Kim, Sungjin
Ma, Yongjie
Spyropoulos, Demetri D.
Beharry, Zanna
Huang, Jiaoti
Fernandez Zapico, Martin Ernesto
Cai, Houjian
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv GTPase Kras (KRAS)
Hedgehog signaling pathway
androgen receptor
p63
prostate cancer
topic GTPase Kras (KRAS)
Hedgehog signaling pathway
androgen receptor
p63
prostate 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 Although the differentiation of oncogenically transformed basal progenitor cells is one of the key steps in prostate tumorigenesis, the mechanisms mediating this cellular process are still largely unknown. Here we demonstrate that an expanded p63+ and CK5+ basal/progenitor cell population, induced by the concomitant activation of oncogenic Kras(G12D) and androgen receptor (AR) signaling, underwent cell differentiation in vivo. The differentiation process led to suppression of p63-expressing cells with a decreased number of CK5+ basal cells but an increase of CK8+ luminal tumorigenic cells and revealed a hierarchal lineage pattern consisting of p63+/CK5+ progenitor, CK5+/CK8+ transitional progenitor, and CK8+ differentiated luminal cells. Further analysis of the phenotype showed that Kras-AR axis-induced tumorigenesis was mediated by Gli transcription factors. Combined blocking of the activators of this family of proteins (Gli1 and Gli2) inhibited the proliferation of p63+ and CK5+ basal/progenitor cells and development of tumors. Finally, we identified that Gli1 and Gli2 exhibited different functions in the regulation of p63 expression or proliferation of p63+ cells in Kras-AR driven tumors. Gli2, but not Gli1, transcriptionally regulated the expression levels of p63 and prostate sphere formation. Our study provides evidence of a novel mechanism mediating pathological dysregulation of basal/progenitor cells through the differential activation of the Gli transcription factors. Also, these findings define Gli proteins as new downstream mediators of the Kras-AR axis in prostate carcinogenesis and open a potential therapeutic avenue of targeting prostate cancer progression by inhibiting Gli signaling.
Fil: Wu, Meng. University of Georgia; Grecia
Fil: Ingram, Lishann. University of Georgia; Grecia
Fil: Tolosa, Ezequiel Julian. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Mayo Clinic; Estados Unidos
Fil: Vera, Renzo Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Mayo Clinic; Estados Unidos
Fil: Li, Qianjin. University of Georgia; Grecia
Fil: Kim, Sungjin. University of Georgia; Grecia
Fil: Ma, Yongjie. University of Georgia; Grecia
Fil: Spyropoulos, Demetri D.. Medical University of South Carolina; Estados Unidos
Fil: Beharry, Zanna. Florida Gulf Coast University; Estados Unidos
Fil: Huang, Jiaoti. University of Duke; Estados Unidos
Fil: Fernandez Zapico, Martin Ernesto. Mayo Clinic; Estados Unidos
Fil: Cai, Houjian. University of Georgia; Grecia
description Although the differentiation of oncogenically transformed basal progenitor cells is one of the key steps in prostate tumorigenesis, the mechanisms mediating this cellular process are still largely unknown. Here we demonstrate that an expanded p63+ and CK5+ basal/progenitor cell population, induced by the concomitant activation of oncogenic Kras(G12D) and androgen receptor (AR) signaling, underwent cell differentiation in vivo. The differentiation process led to suppression of p63-expressing cells with a decreased number of CK5+ basal cells but an increase of CK8+ luminal tumorigenic cells and revealed a hierarchal lineage pattern consisting of p63+/CK5+ progenitor, CK5+/CK8+ transitional progenitor, and CK8+ differentiated luminal cells. Further analysis of the phenotype showed that Kras-AR axis-induced tumorigenesis was mediated by Gli transcription factors. Combined blocking of the activators of this family of proteins (Gli1 and Gli2) inhibited the proliferation of p63+ and CK5+ basal/progenitor cells and development of tumors. Finally, we identified that Gli1 and Gli2 exhibited different functions in the regulation of p63 expression or proliferation of p63+ cells in Kras-AR driven tumors. Gli2, but not Gli1, transcriptionally regulated the expression levels of p63 and prostate sphere formation. Our study provides evidence of a novel mechanism mediating pathological dysregulation of basal/progenitor cells through the differential activation of the Gli transcription factors. Also, these findings define Gli proteins as new downstream mediators of the Kras-AR axis in prostate carcinogenesis and open a potential therapeutic avenue of targeting prostate cancer progression by inhibiting Gli signaling.
publishDate 2016
dc.date.none.fl_str_mv 2016-12
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/11336/61772
Wu, Meng; Ingram, Lishann; Tolosa, Ezequiel Julian; Vera, Renzo Emanuel; Li, Qianjin; et al.; Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axis; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 291; 49; 12-2016; 25749-25760
0021-9258
CONICET Digital
CONICET
url http://hdl.handle.net/11336/61772
identifier_str_mv Wu, Meng; Ingram, Lishann; Tolosa, Ezequiel Julian; Vera, Renzo Emanuel; Li, Qianjin; et al.; Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axis; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 291; 49; 12-2016; 25749-25760
0021-9258
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M116.753129
info:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/content/291/49/25749
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 American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
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 13.13397

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