Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression
Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression
复制标题
DOI：
10.3390/cancers12051340
复制
发表时间：
2020-05-01
期刊：
影响因子：
5.2
通讯作者：
Figueroa, Angelica
中科院分区：
文献类型：
--
作者：
Martinez-Iglesias, Olaia;Casas-Pais, Alba;Figueroa, Angelica
E3泛素连接酶Hakai对E-cadherin的泛素化和随后的降解的需求与增强的上皮-间质转化（EMT）、肿瘤进展和癌转移相关。迄今为止，大多数报道的EMT相关抑制剂不是为了抗EMT目的而开发的，而是间接影响EMT。另一方面，E3泛素连接酶最近已成为有希望的治疗靶点，因为它们的特异性抑制将防止更广泛的副作用。在此背景下，进行虚拟筛选以鉴定Hakai的新型特异性抑制剂，其靶向磷酸酪氨酸结合口袋，磷酸化-E-钙粘蛋白特异性结合在该口袋中。我们选择了一个候选抑制剂，Hakin-1，它表现出对Hakai诱导的泛素化的重要影响。Hakin-1还在体外（结直肠癌细胞系）和体内（肿瘤异种移植小鼠模型）抑制癌生长和肿瘤进展，在小鼠中没有明显的全身毒性。我们的研究结果首次表明，靶向E3泛素连接酶Hakai的小分子puplatin抑制了E-cadherin的Hakai依赖性泛素化，对EMT过程产生了影响。这代表了未来开发有效治疗药物以预防或抑制癌肿瘤进展的重要一步。
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.