Phosphorylation of androgen receptor by mTORC1 promotes liver steatosis and tumorigenesis.

Autor: Ren QN; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineSun Yat-Sen University Cancer CenterGuangzhouChina.; Department of Nasopharyngeal CarcinomaSun Yat-Sen University Cancer CenterGuangzhouChina., Zhang H; Rutgers Cancer Institute of New Jersey and Department of PharmacologyRobert Wood Johnson Medical SchoolRutgers UniversityNew BrunswickNew JerseyUSA., Sun CY; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineSun Yat-Sen University Cancer CenterGuangzhouChina., Zhou YF; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineSun Yat-Sen University Cancer CenterGuangzhouChina., Yang XF; Department of GastroenterologyAffiliated Nanhua Hospital, Hengyang Medical College, University of South ChinaHengyangChina., Long JW; Department of Hepatobiliary SurgeryAffiliated Nanhua Hospital, Hengyang Medical College, University of South ChinaHengyangChina., Li XX; Precision Medicine InstituteThe First Affiliated Hospital, Sun Yat-Sen UniversityGuangzhouChina., Mai SJ; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineSun Yat-Sen University Cancer CenterGuangzhouChina., Zhang MY; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineSun Yat-Sen University Cancer CenterGuangzhouChina., Zhang HZ; Department of PathologySun Yat-Sen University Cancer CenterGuangzhouChina., Mai HQ; Department of Nasopharyngeal CarcinomaSun Yat-Sen University Cancer CenterGuangzhouChina., Chen MS; Department of Liver SurgerySun Yat-Sen University Cancer CenterGuangzhouChina., Zheng XFS; Rutgers Cancer Institute of New Jersey and Department of PharmacologyRobert Wood Johnson Medical SchoolRutgers UniversityNew BrunswickNew JerseyUSA., Wang HY; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineSun Yat-Sen University Cancer CenterGuangzhouChina.
Jazyk: angličtina
Zdroj: Hepatology (Baltimore, Md.) [Hepatology] 2022 May; Vol. 75 (5), pp. 1123-1138. Date of Electronic Publication: 2021 Dec 07.
DOI: 10.1002/hep.32120
Abstrakt: Background and Aims: Androgen receptor (AR) has been reported to play an important role in the development and progression of man's prostate cancer. Hepatocellular carcinoma (HCC) is also male-dominant, but the role of AR in HCC remains poorly understood. Mechanistic target of rapamycin complex 1 (mTORC1) also has been reported to be highly activated in HCC. In this study, we aimed to explore the role of AR phosphorylation and its relationship with mTORC1 in hepatocarcinogenesis.
Approach and Results: In vitro experiment, we observed that mTORC1 interacts with hepatic AR and phosphorylates it at S96 in response to nutrient and mitogenic stimuli in HCC cells. S96 phosphorylation promotes the stability, nuclear localization, and transcriptional activity of AR, which enhances de novo lipogenesis and proliferation in hepatocytes and induces liver steatosis and hepatocarcinogenesis in mice independently and cooperatively with androgen. Furthermore, high AR S96 phosphorylation is observed in human liver steatotic and HCC tissues and is associated with overall survival and disease-free survival, which has been proven as an independent survival predictor for patients with HCC.
Conclusions: AR S96 phosphorylation by mTORC1 drives liver steatosis and HCC development and progression independently and cooperatively with androgen, which not only explains why HCC is man-biased but also provides a target molecule for prevention and treatment of HCC and a potential survival predictor in patients with HCC.
(© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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