Targeting protein degradation as a novel cancer therapeutic strategysmall-molecule inhibitors of the E3 ubiquitin-ligase Hakai

Resumen

Carcinoma is the most common type of cancer, and arises from the malignant transformation of epithelial cells. At the early stages of carcinoma progression, a process known as epithelialmesenchymal transition (EMT) takes place. EMT is characterized by the downregulation of Ecadherin, a tumour suppressor responsible for cell adhesion in the epithelium. The E3 ubiquitinligase Hakai was the first reported posttranslational regulator of the E-cadherin stability, and its importance during tumour progression and disease has been widely demonstrated. E3 ubiquitinligase enzymes have recently emerged as promising therapeutic targets, as their specific inhibition would avoid wider side effects compared to other members of the ubiquitin pathway. EMT has also been associated with other aspects of tumour progression, such as the acquisition of therapeutic resistance or the development of cancer stem cells (CSCs). The aims of this project were the identification and validation of a small-molecule inhibitor for the E3 ubiquitin-ligase Hakai, and the study of the involvement of Hakai in the acquisition CSC properties and other aspects of tumour progression. Results showed that Hakai inhibitor (Hakin-1) reduced Hakaidependent ubiquitination of E-cadherin, showing an important antitumor effect both in vitro and in vivo, therefore being a promising therapeutic agent for cancer treatment through the inhibition of EMT. On the other hand, Hakai may play a role in the development of CSCs, opening a new research field to overcome therapeutic resistance.