Abstract
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.
Highlights
Carcinoma, the most common type of cancer, arises from epithelial cells
We previously showed that Hakai overexpression in immortalized epithelial MDCK cells (Hakai-MDCK) induced a fibroblastic-like phenotype accompanied by the loss of E-cadherin-based cell–cell contacts [38,40]
As an important precondition of metastasis, the targeted against epithelial-to-mesenchymal transition (EMT), we focused our attention on the E3 ubiquitin-ligase Hakai, a post-translational
Summary
The most common type of cancer, arises from epithelial cells. During carcinoma progression, epithelial cells acquire a high degree of plasticity and the ability to reversibly changeCancers 2020, 12, 1340; doi:10.3390/cancers12051340 www.mdpi.com/journal/cancersCancers 2020, 12, 1340 phenotype [1,2]. The most common type of cancer, arises from epithelial cells. Epithelial cells can undergo a program named epithelial-to-mesenchymal transition (EMT), priming their migration from the primary tumour, their dissemination and metastasis formation [3,4]. EMT has been associated with tumour initiation, migration, malignant progression, stemness, intravasation, metastasis, and drug resistance, with important clinical implications [5,6]. EMT is characterized by the loss of E-cadherin epithelial marker and the acquisition of mesenchymal markers, such as N-cadherin and vimentin. The loss of E-cadherin, the best characterized member of cadherins at cell–cell contacts in epithelial cells, is a hallmark of EMT but is associated with the transition from adenoma to carcinoma [7,8]
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