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Open AccessArticle

Heat Shock Protein 90 Chaperone Regulates the E3 Ubiquitin-Ligase Hakai Protein Stability

1
Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain
2
Istituto per la Ricerca e l’Innovazione Biomedica (IRIB)—CNR di Palermo, Via Ugo La Malfa 153, 90146 Palermo, Italy
3
Pathology Department and A Coruña Biobank from Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain
4
Clinical Oncology Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(1), 215; https://doi.org/10.3390/cancers12010215
Received: 17 December 2019 / Revised: 9 January 2020 / Accepted: 12 January 2020 / Published: 15 January 2020
(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)
The E3 ubiquitin-ligase Hakai binds to several tyrosine-phosphorylated Src substrates, including the hallmark of the epithelial-to-mesenchymal transition E-cadherin, and signals for degradation of its specific targets. Hakai is highly expressed in several human cancers, including colon cancer, and is considered as a drug target for cancer therapy. Here, we report a link between Hakai and the heat shock protein 90 (Hsp90) chaperone complex. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. Hsp90 inhibitors specifically interfere with the association with its Hsp90 client proteins, and exhibit potent anti-cancer properties. By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Pharmacological inhibition of Hsp90 with geldanamycin results in the degradation of Hakai in a lysosome-dependent manner. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. We also show that geldanamycin suppresses cell motility at least in part through its action on Hakai expression. Taken together, our results identify Hakai as a novel Hsp90 client protein and shed light on the regulation of Hakai stability. Our results open the possibility to the potential use of Hsp90 inhibitors for colorectal cancer therapy through its action on Hakai client protein of Hsp90. View Full-Text
Keywords: Hsp90 chaperone; E3 ubiquitin-ligase Hakai; targeted therapy; colon cancer Hsp90 chaperone; E3 ubiquitin-ligase Hakai; targeted therapy; colon cancer
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Díaz-Díaz, A.; Roca-Lema, D.; Casas-Pais, A.; Romay, G.; Colombo, G.; Concha, Á.; Graña, B.; Figueroa, A. Heat Shock Protein 90 Chaperone Regulates the E3 Ubiquitin-Ligase Hakai Protein Stability. Cancers 2020, 12, 215.

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