G protein-coupled receptor kinase 2 (GRK2) promotes breast tumorigenesis through a HDAC6-Pin1 Axis
Author
Nogués, Laura; Reglero, Clara; Rivas, Verónica; Salcedo, Alicia; Lafarga, Vanesa; Neves, María; Ramos, Paula; Mendiola, Marta; Berjón, Alberto; Stamatakis Andriani, Konstantinos; Zhou, Xiao Zhen; Lu, Kun Ping; Hardisson Hernáez, David Alonso; Mayor Menéndez, Federico; Penela Márquez, PetronilaEntity
UAM. Departamento de Anatomía Patológica; Centro de Biología Molecular Severo Ochoa (CBM); Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)Publisher
Elsevier B.V.Date
2016-11-01Citation
10.1016/j.ebiom.2016.09.030
EBioMedicine 13 (2016): 132–145
ISSN
2352-3964DOI
10.1016/j.ebiom.2016.09.030Funded by
Our laboratory is funded by grants from Ministerio de Economía y Competitividad (SAF2011-23800 and SAF2014-55511R), the European Union (H2020-MSCA Programme, Grant agreement 64183-ONCORNET), The Cardiovascular Network of Ministerio Sanidad y Consumo-Instituto Carlos III (RD12/0042/0012), Comunidad de Madrid (S-2010/BMD-2332) to F.M and Instituto Carlos III (PI11/00859, PI14-00435, PIE-13-00041), Fundación Ramón Areces and Fundación Rodríguez Pascual to P.P. Dr.MartaMendiola is supported by a postdoctoral research contract of Fondo de Investigación Sanitaria (FIS) (‘Sara Borrell’ Program), Instituto de Salud Carlos IIIProject
Gobierno de España. SAF2011-23800; Gobierno de España. SAF2014-55511R; info:eu-repo/grantAgreement/EC/FP7/64183; Comunidad de Madrid. S-2010/BMD-2332/INDISNETEditor's Version
http://dx.doi.org/10.1016/j.ebiom.2016.09.030Subjects
Acetylation; Breast transformation; Cancer; GRK2; HDAC6; Pin1; MedicinaRights
© 2016 The AuthorsEsta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
In addition to oncogenic drivers, signaling nodes can critically modulate cancer-related cellular networks to strength tumor hallmarks. We identify G-protein-coupled receptor kinase 2 (GRK2) as a relevant player in breast cancer. GRK2 is up-regulated in breast cancer cell lines, in spontaneous tumors in mice, and in a proportion of invasive ductal carcinoma patients. Increased GRK2 functionality promotes the phosphorylation and activation of the Histone Deacetylase 6 (HDAC6) leading to de-acetylation of the Prolyl Isomerase Pin1, a central modulator of tumor progression, thereby enhancing its stability and functional interaction with key mitotic regulators. Interestingly, a correlation between GRK2 expression and Pin1 levels and de-acetylation status is detected in breast cancer patients. Activation of the HDAC6-Pin1 axis underlies the positive effects of GRK2 on promoting growth factor signaling, cellular proliferation and anchorage-independent growth in both luminal and basal breast cancer cells. Enhanced GRK2 levels promote tumor growth in mice, whereas GRK2 down-modulation sensitizes cells to therapeutic drugs and abrogates tumor formation. Our data suggest that GRK2 acts as an important onco-modulator by strengthening the functionality of key players in breast tumorigenesis such as HDAC6 and Pin1.
Files in this item
Google Scholar:Nogués, Laura
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Reglero, Clara
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Rivas, Verónica
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Salcedo, Alicia
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Lafarga, Vanesa
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Neves, María
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Ramos, Paula
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Mendiola, Marta
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Berjón, Alberto
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Stamatakis Andriani, Konstantinos
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Zhou, Xiao Zhen
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Lu, Kun Ping
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Hardisson Hernáez, David Alonso
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Mayor Menéndez, Federico
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Penela Márquez, Petronila
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