AKT1 regulates UHRF1 protein stability and promotes the resistance to abiraterone in prostate cancer

被引:12
|
作者
Fu, Yongming [1 ,2 ,3 ]
Cao, Tuoyu [4 ,5 ]
Zou, Xiaorui [6 ]
Ye, Yubing [6 ]
Liu, Youhong [4 ,5 ]
Peng, Yuchong [1 ,2 ,3 ]
Deng, Tanggang [1 ,2 ,3 ]
Yin, Linglong [1 ,2 ,6 ]
Li, Xiong [1 ,2 ,6 ]
机构
[1] Guangdong Pharmaceut Univ, Affiliated Hosp 1, Key Lab Clin Precis Pharm Guangdong Higher Educ In, Guangzhou, Peoples R China
[2] Guangdong Pharmaceut Univ, Affiliated Hosp 1, Key Specialty Clin Pharm, Guangzhou, Peoples R China
[3] Guangdong Pharmaceut Univ, NMPA Key Lab Technol Res & Evaluat Pharmacovigilan, Guangzhou, Peoples R China
[4] Cent South Univ, Xiangya Hosp, Ctr Mol Med, Dept Oncol, Changsha, Peoples R China
[5] Cent South Univ, Xiangya Hosp, Hunan Key Lab Mol Radiat Oncol, Changsha, Peoples R China
[6] Guangdong Pharmaceut Univ, Sch Clin Pharm, Guangzhou, Peoples R China
基金
中国国家自然科学基金;
关键词
INCREASED SURVIVAL; DNA METHYLATION; PHOSPHORYLATION; REPLICATION; METASTASIS; MECHANISMS; MARKER;
D O I
10.1038/s41389-022-00446-y
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
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页数:12
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