机构：[1]Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China[2]Department of Urology, University of PittsburghCancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA[3]Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School ofMedicine, Shanghai, PR China[4]Department of Urology, The Second Xiangya Hospital of Central South University, Hunan, China[5]The third Xiangya Hospital of Central SouthUniversity, Changsha, China[6]Department of Pathology, NYU School of Medicine, New York, NY, USA[7]Transcriptomics Lab, Division of Plant Biotechnology, SKUAST-K, Shalimar,Srinagar, J&K, India[8]Department of Geriatrics, Guangzhou General Hospital of Guangzhou Military Command[G]uangdong Provincial Key Laboratory of Geriatric Infection andOrgan Function Support[G]uangzhou Key Laboratory of Geriatric Infection and Organ Function Support[G]uangzhou, Guangdong, China[9]Cancer Center, Traditional ChineseMedicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong, China[10]Center for Translational Medicine, Guangxi Medical University, Nanning, Guangxi,China University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA[11]Department of Molecular Pharmacology and Chemical Biology,University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA[12]Department of Pathology, University of Pittsburgh CancerInstitute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Androgen receptor (AR) activation is critical for prostate cancer (PCa) development and progression, including castration resistance. The nuclear export signal of AR (NESAR) has an important role in AR intracellular trafficking and proteasome-dependent degradation. Here, we identified the RNA helicase DHX15 as a novel AR co-activator using a yeast mutagenesis screen and revealed that DHX15 regulates AR activity by modulating E3 ligase Siah2-mediated AR ubiquitination independent of its ATPase activity. DHX15 and Siah2 form a complex with AR, through NESAR. DHX15 stabilized Siah2 and enhanced its E3 ubiquitin-ligase activity, resulting in AR activation. Importantly, DHX15 was upregulated in PCa specimens and its expression was correlated with Gleason scores and prostate-specific antigen recurrence. Furthermore, DHX15 immunostaining correlated with Siah2. Finally, DHX15 knockdown inhibited the growth of C4-2 prostate tumor xenografts in mice. Collectively, our data argue that DHX15 enhances AR transcriptional activity and contributes to PCa progression through Siah2.
基金：
NIH R01 CA186780 (ZW), NIH R01 CA108675 (ZW), ACS #PF-05-229-01-CSM (MMN), the
Department of Defense Prostate Cancer Research Program Award No W81XWH-14-2-
0182, W81XWH-14-2-0183, W81XWH-14-2-0185, W81XWH-14-2-0186, and
W81XWH-15-2-0062 PCBN, National Nature Science Foundation of China
#81402091 (YJ), and National Natural Science Foundation of China Key Project
81130046 (JZ) and 2013GXNSFEA053004 (JZ). This work was also supported by a
post-doctoral fellowship from the Urology Care Foundation of the American
Urological Association (DW), the Mellam Family Fellowship (DW and KZM), the
Tippens Scholarship (LEP) and NIH R50 CA211242-01 (LEP). In addition, this research
was supported by the UPCI Animal Facility, Vector Core and Tissue and Research
Pathology Services (TARPS) funded through NCI CCSG P30CA047904.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|1 区医学
小类|1 区遗传学2 区生化与分子生物学2 区细胞生物学2 区肿瘤学
最新[2025]版：
大类|1 区医学
小类|1 区生化与分子生物学1 区遗传学2 区细胞生物学2 区肿瘤学
第一作者：
第一作者机构：[1]Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China[2]Department of Urology, University of PittsburghCancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
通讯作者：
通讯机构：[1]Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China[2]Department of Urology, University of PittsburghCancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA[11]Department of Molecular Pharmacology and Chemical Biology,University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA[12]Department of Pathology, University of Pittsburgh CancerInstitute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.[*1]Department of Urology, Department of Molecular Pharmacology and Chemical Biology and Department of Pathology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA
推荐引用方式(GB/T 7714)：
Jing Y,Nguyen M M,Wang D,et al.DHX15 promotes prostate cancer progression by stimulating Siah2-mediated ubiquitination of androgen receptor.[J].Oncogene.2018,37(5):638-650.doi:10.1038/onc.2017.371.
APA：
Jing Y,Nguyen M M,Wang D,Pascal L E,Guo W...&Wang Z.(2018).DHX15 promotes prostate cancer progression by stimulating Siah2-mediated ubiquitination of androgen receptor..Oncogene,37,(5)
MLA：
Jing Y,et al."DHX15 promotes prostate cancer progression by stimulating Siah2-mediated ubiquitination of androgen receptor.".Oncogene 37..5(2018):638-650
医学