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Open AccessArticle

Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression

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
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
3
Computational Chemistry-UK, RD Platform Technology & Science, GSK Medicines Research Centre, Hertfordshire SG12 0DP, UK
4
Area of Pharmacology, Department of Biomedical Sciences and “Unidad Asociada IQM-CSIC”, School of Medicine and Health Sciences, University of Alcalá de Henares, 28805 Alcalá de Henares, Spain
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(5), 1340; https://doi.org/10.3390/cancers12051340
Received: 24 April 2020 / Revised: 18 May 2020 / Accepted: 21 May 2020 / Published: 23 May 2020
(This article belongs to the Special Issue Targeted Cancer Therapy)
The requirement of the E3 ubiquitin-ligase Hakai for the ubiquitination and subsequent degradation of E-cadherin has been associated with enhanced epithelial-to-mesenchymal transition (EMT), tumour progression and carcinoma metastasis. To date, most of the reported EMT-related inhibitors were not developed for anti-EMT purposes, but indirectly affect EMT. On the other hand, E3 ubiquitin-ligase enzymes have recently emerged as promising therapeutic targets, as their specific inhibition would prevent wider side effects. Given this background, a virtual screening was performed to identify novel specific inhibitors of Hakai, targeted against its phosphotyrosine-binding pocket, where phosphorylated-E-cadherin specifically binds. We selected a candidate inhibitor, Hakin-1, which showed an important effect on Hakai-induced ubiquitination. Hakin-1 also inhibited carcinoma growth and tumour progression both in vitro, in colorectal cancer cell lines, and in vivo, in a tumour xenograft mouse model, without apparent systemic toxicity in mice. Our results show for the first time that a small molecule putatively targeting the E3 ubiquitin-ligase Hakai inhibits Hakai-dependent ubiquitination of E-cadherin, having an impact on the EMT process. This represents an important step forward in a future development of an effective therapeutic drug to prevent or inhibit carcinoma tumour progression. View Full-Text
Keywords: anticancer therapy; small-molecule inhibitor; epithelial-to-mesenchymal transition (EMT); E-cadherin; E3 ubiquitin-ligase; Hakai anticancer therapy; small-molecule inhibitor; epithelial-to-mesenchymal transition (EMT); E-cadherin; E3 ubiquitin-ligase; Hakai
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Martinez-Iglesias, O.; Casas-Pais, A.; Castosa, R.; Díaz-Díaz, A.; Roca-Lema, D.; Concha, Á.; Cortés, Á.; Gago, F.; Figueroa, A. Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression. Cancers 2020, 12, 1340.

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