SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancer

Autores
Enriqué Steinberg, Juliana Haydeé; Rossi, Fabiana Alejandra; Magliozzi, Roberto; Yuniati, Laurensia; Santucci, Matteo; Rossi, Mario; Guardavaccaro, Daniele; Lauriola, Angela
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with metastasis, high recurrence rate, and poor survival. The basic helix-loop-helix transcription factor SHARP1 (Split and Hairy-related Protein 1) has been identified as a suppressor of the metastatic behavior of TNBC. SHARP1 blocks the invasive phenotype of TNBC by inhibiting hypoxia-inducible factors and itsloss correlates with poor survival of breast cancer patients. Here, we show that SHARP1 is an unstable protein that is targeted for proteasomal degradation by the E3 ubiquitin ligase complex SCFβTrCP. SHARP1 recruits βTrCP via a phosphodegron encompassing Ser240 and Glu245 which are required for SHARP1 ubiquitylation and degradation. Furthermore, mice injected with TNBC cellsexpressing the non-degradable SHARP1(S240A/E245A) mutant display reduced tumor growth and increased tumor-free survival. Our study suggests that targeting the βTrCP-dependent degradation of SHARP1 represents a therapeutic strategy in TNBC.
Fil: Enriqué Steinberg, Juliana Haydeé. Universita Di Verona. Dipartimento Scientífico E Tecnológico; Italia
Fil: Rossi, Fabiana Alejandra. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Magliozzi, Roberto. Hubrecht Institute-knaw; Países Bajos
Fil: Yuniati, Laurensia. Hubrecht Institute-knaw; Países Bajos
Fil: Santucci, Matteo. Universita Di Verona. Dipartimento Scientífico E Tecnológico; Italia
Fil: Rossi, Mario. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Guardavaccaro, Daniele. Universita Di Verona. Dipartimento Scientífico E Tecnológico; Italia
Fil: Lauriola, Angela. Universita Di Verona. Dipartimento Scientífico E Tecnológico; Italia
Materia
TNBC
ubiquitin
cell migration
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:11336/255923
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/255923
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancerEnriqué Steinberg, Juliana HaydeéRossi, Fabiana AlejandraMagliozzi, RobertoYuniati, LaurensiaSantucci, MatteoRossi, MarioGuardavaccaro, DanieleLauriola, AngelaTNBCubiquitincell migrationhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with metastasis, high recurrence rate, and poor survival. The basic helix-loop-helix transcription factor SHARP1 (Split and Hairy-related Protein 1) has been identified as a suppressor of the metastatic behavior of TNBC. SHARP1 blocks the invasive phenotype of TNBC by inhibiting hypoxia-inducible factors and itsloss correlates with poor survival of breast cancer patients. Here, we show that SHARP1 is an unstable protein that is targeted for proteasomal degradation by the E3 ubiquitin ligase complex SCFβTrCP. SHARP1 recruits βTrCP via a phosphodegron encompassing Ser240 and Glu245 which are required for SHARP1 ubiquitylation and degradation. Furthermore, mice injected with TNBC cellsexpressing the non-degradable SHARP1(S240A/E245A) mutant display reduced tumor growth and increased tumor-free survival. Our study suggests that targeting the βTrCP-dependent degradation of SHARP1 represents a therapeutic strategy in TNBC.Fil: Enriqué Steinberg, Juliana Haydeé. Universita Di Verona. Dipartimento Scientífico E Tecnológico; ItaliaFil: Rossi, Fabiana Alejandra. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Magliozzi, Roberto. Hubrecht Institute-knaw; Países BajosFil: Yuniati, Laurensia. Hubrecht Institute-knaw; Países BajosFil: Santucci, Matteo. Universita Di Verona. Dipartimento Scientífico E Tecnológico; ItaliaFil: Rossi, Mario. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Guardavaccaro, Daniele. Universita Di Verona. Dipartimento Scientífico E Tecnológico; ItaliaFil: Lauriola, Angela. Universita Di Verona. Dipartimento Scientífico E Tecnológico; ItaliaSpringer2023-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/255923Enriqué Steinberg, Juliana Haydeé; Rossi, Fabiana Alejandra; Magliozzi, Roberto; Yuniati, Laurensia; Santucci, Matteo; et al.; SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancer; Springer; Cell Death & Disease; 14; 11; 11-2023; 1-72041-4889CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41419-023-06253-6info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:06:26Zoai:ri.conicet.gov.ar:11336/255923instacron: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:34982025-10-15 15:06:26.3CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancer
title SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancer
spellingShingle SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancer
Enriqué Steinberg, Juliana Haydeé
TNBC
ubiquitin
cell migration
title_short SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancer
title_full SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancer
title_fullStr SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancer
title_full_unstemmed SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancer
title_sort SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancer
dc.creator.none.fl_str_mv Enriqué Steinberg, Juliana Haydeé
Rossi, Fabiana Alejandra
Magliozzi, Roberto
Yuniati, Laurensia
Santucci, Matteo
Rossi, Mario
Guardavaccaro, Daniele
Lauriola, Angela
author Enriqué Steinberg, Juliana Haydeé
author_facet Enriqué Steinberg, Juliana Haydeé
Rossi, Fabiana Alejandra
Magliozzi, Roberto
Yuniati, Laurensia
Santucci, Matteo
Rossi, Mario
Guardavaccaro, Daniele
Lauriola, Angela
author_role author
author2 Rossi, Fabiana Alejandra
Magliozzi, Roberto
Yuniati, Laurensia
Santucci, Matteo
Rossi, Mario
Guardavaccaro, Daniele
Lauriola, Angela
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv TNBC
ubiquitin
cell migration
topic TNBC
ubiquitin
cell migration
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with metastasis, high recurrence rate, and poor survival. The basic helix-loop-helix transcription factor SHARP1 (Split and Hairy-related Protein 1) has been identified as a suppressor of the metastatic behavior of TNBC. SHARP1 blocks the invasive phenotype of TNBC by inhibiting hypoxia-inducible factors and itsloss correlates with poor survival of breast cancer patients. Here, we show that SHARP1 is an unstable protein that is targeted for proteasomal degradation by the E3 ubiquitin ligase complex SCFβTrCP. SHARP1 recruits βTrCP via a phosphodegron encompassing Ser240 and Glu245 which are required for SHARP1 ubiquitylation and degradation. Furthermore, mice injected with TNBC cellsexpressing the non-degradable SHARP1(S240A/E245A) mutant display reduced tumor growth and increased tumor-free survival. Our study suggests that targeting the βTrCP-dependent degradation of SHARP1 represents a therapeutic strategy in TNBC.
Fil: Enriqué Steinberg, Juliana Haydeé. Universita Di Verona. Dipartimento Scientífico E Tecnológico; Italia
Fil: Rossi, Fabiana Alejandra. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Magliozzi, Roberto. Hubrecht Institute-knaw; Países Bajos
Fil: Yuniati, Laurensia. Hubrecht Institute-knaw; Países Bajos
Fil: Santucci, Matteo. Universita Di Verona. Dipartimento Scientífico E Tecnológico; Italia
Fil: Rossi, Mario. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Guardavaccaro, Daniele. Universita Di Verona. Dipartimento Scientífico E Tecnológico; Italia
Fil: Lauriola, Angela. Universita Di Verona. Dipartimento Scientífico E Tecnológico; Italia
description Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with metastasis, high recurrence rate, and poor survival. The basic helix-loop-helix transcription factor SHARP1 (Split and Hairy-related Protein 1) has been identified as a suppressor of the metastatic behavior of TNBC. SHARP1 blocks the invasive phenotype of TNBC by inhibiting hypoxia-inducible factors and itsloss correlates with poor survival of breast cancer patients. Here, we show that SHARP1 is an unstable protein that is targeted for proteasomal degradation by the E3 ubiquitin ligase complex SCFβTrCP. SHARP1 recruits βTrCP via a phosphodegron encompassing Ser240 and Glu245 which are required for SHARP1 ubiquitylation and degradation. Furthermore, mice injected with TNBC cellsexpressing the non-degradable SHARP1(S240A/E245A) mutant display reduced tumor growth and increased tumor-free survival. Our study suggests that targeting the βTrCP-dependent degradation of SHARP1 represents a therapeutic strategy in TNBC.
publishDate 2023
dc.date.none.fl_str_mv 2023-11
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/11336/255923
Enriqué Steinberg, Juliana Haydeé; Rossi, Fabiana Alejandra; Magliozzi, Roberto; Yuniati, Laurensia; Santucci, Matteo; et al.; SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancer; Springer; Cell Death & Disease; 14; 11; 11-2023; 1-7
2041-4889
CONICET Digital
CONICET
url http://hdl.handle.net/11336/255923
identifier_str_mv Enriqué Steinberg, Juliana Haydeé; Rossi, Fabiana Alejandra; Magliozzi, Roberto; Yuniati, Laurensia; Santucci, Matteo; et al.; SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancer; Springer; Cell Death & Disease; 14; 11; 11-2023; 1-7
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/s41419-023-06253-6
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 Springer
publisher.none.fl_str_mv Springer
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_ 1846083207544438784
score 13.22299

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