Next Article in Journal
Small Molecule KRAS Inhibitors: The Future for Targeted Pancreatic Cancer Therapy?
Next Article in Special Issue
An Anti-PSMA Immunotoxin Reduces Mcl-1 and Bcl2A1 and Specifically Induces in Combination with the BAD-Like BH3 Mimetic ABT-737 Apoptosis in Prostate Cancer Cells
Previous Article in Journal
Regulation of Src Family Kinases during Colorectal Cancer Development and Its Clinical Implications
Previous Article in Special Issue
All-Trans Retinoic Acid Stimulates Viral Mimicry, Interferon Responses and Antigen Presentation in Breast-Cancer Cells
Article

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
Show Figures

Figure 1

MDPI and ACS Style

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. https://doi.org/10.3390/cancers12051340

AMA Style

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(5):1340. https://doi.org/10.3390/cancers12051340

Chicago/Turabian Style

Martinez-Iglesias, Olaia, Alba Casas-Pais, Raquel Castosa, Andrea Díaz-Díaz, Daniel Roca-Lema, Ángel Concha, Álvaro Cortés, Federico Gago, and Angélica Figueroa. 2020. "Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression" Cancers 12, no. 5: 1340. https://doi.org/10.3390/cancers12051340

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop