Fu Yongming, Cao Tuoyu, Zou Xiaorui, Ye Yubing, Liu Youhong, Peng Yuchong, Deng Tanggang, Yin Linglong, Li Xiong
Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, China.
Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China.
Oncogenesis. 2023 Jan 2;12(1):1. doi: 10.1038/s41389-022-00446-y.
Oncogenic activation of PI3K/AKT signaling pathway, together with epigenetic aberrations are the characters of castration-resistant prostate cancer (CRPC). UHRF1 as a key epigenetic regulator, plays a critical role in prostate cancer (PCa) development, and its expression is positively correlated with the degree of malignancy. In this present study we investigated the potential regulatory mechanism of AKT1 on UHRF1, and further validated the in vitro and in vivo anticancer efficacy of AKT phosphorylation inhibitor MK2206 in combination with abiraterone. Both UHRF1 and p-AKT aberrantly overexpressed in the abiraterone-resistant PCa cells. Further studies revealed that AKT1 protein interacts with UHRF1, and AKT1 directly phosphorylates UHRF1 via the site Thr-210. MK2206 induced UHRF1 protein degradation by inhibiting AKT1-induced UHRF1 phosphorylation, and then reduced the interaction between UHRF1 and deubiquitinase USP7, while promoted the interaction between UHRF1 and E3 ubiquitin protein ligase BTRC. MK2206 significantly promoted the sensitivity of abiraterone-refractory PCa cells and xenografts to abiraterone by decreasing UHRF1 protein level, and reversed the phenotype of NEPC, evently induced cellular senescence and cell apoptosis. Altogether, our present study for the first time revealed a novel molecular mechanism of abiraterone resistance through PI3K/AKT-UHRF1 pathway, and provided a novel therapeutic modality by targeting PI3K/AKT1 to promote the drug sensitivity of abiraterone in PCa patients.
PI3K/AKT信号通路的致癌激活以及表观遗传异常是去势抵抗性前列腺癌（CRPC）的特征。UHRF1作为一种关键的表观遗传调节因子，在前列腺癌（PCa）发展中起关键作用，其表达与恶性程度呈正相关。在本研究中，我们研究了AKT1对UHRF1的潜在调控机制，并进一步验证了AKT磷酸化抑制剂MK2206与阿比特龙联合使用的体外和体内抗癌疗效。UHRF1和p-AKT在阿比特龙耐药的PCa细胞中均异常过表达。进一步研究表明，AKT1蛋白与UHRF1相互作用，且AKT1通过苏氨酸-210位点直接磷酸化UHRF1。MK2206通过抑制AKT1诱导的UHRF1磷酸化来诱导UHRF1蛋白降解，进而减少UHRF1与去泛素化酶USP7之间的相互作用，同时促进UHRF1与E3泛素蛋白连接酶BTRC之间的相互作用。MK2206通过降低UHRF1蛋白水平显著提高了阿比特龙难治性PCa细胞和异种移植物对阿比特龙的敏感性，并逆转了神经内分泌前列腺癌（NEPC）的表型，最终诱导细胞衰老和细胞凋亡。总之，我们的研究首次揭示了通过PI3K/AKT-UHRF1途径导致阿比特龙耐药的新分子机制，并提供了一种通过靶向PI3K/AKT1来提高PCa患者对阿比特龙药物敏感性的新治疗方式。
