Phosphorylation of the androgen receptor at Ser81 is co-sustained by CDK1 and CDK9 and leads to AR-mediated transactivation in prostate cancer

作者全名："Gao, XinTao; Liang, Jiaqian; Wang, LiYang; Zhang, Zhaoyang; Yuan, Penghui; Wang, Jiaxin; Gao, Yanfei; Ma, Fen; Calagua, Carla; Ye, Huihui; Voznesensky, Olga; Wang, Shaogang; Wang, Tao; Liu, Jihong; Chen, Shaoyong; Liu, Xiaming"

作者地址："[Gao, XinTao; Yuan, Penghui; Wang, Jiaxin; Wang, Shaogang; Wang, Tao; Liu, Jihong; Liu, Xiaming] Huazhong Univ Sci & Technol, Tongji Hosp, Dept Urol, Tongji Med Coll, Wuhan, Peoples R China; [Liang, Jiaqian; Wang, LiYang; Ma, Fen; Calagua, Carla; Voznesensky, Olga; Chen, Shaoyong] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Hematol Oncol Div, Boston, MA 02115 USA; [Liang, Jiaqian] Huazhong Univ Sci & Technol, Wuhan Hosp 1, Tongji Med Coll, Wuhan, Peoples R China; [Zhang, Zhaoyang] Hubei Univ Med, Inst Basic Med Sci, Dept Biochem & Mol Biol, Coll Basic Med, Shiyan, Peoples R China; [Gao, Yanfei] Chongqing Med Univ, Affiliated Hosp 2, Dept Orthopaed Surg, Chongqing, Peoples R China; [Ye, Huihui] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA; [Ye, Huihui] Univ Calif Los Angeles, Dept Pathol, Los Angeles, CA 90024 USA"

通信作者："Liu, XM (corresponding author), Tongji Hosp, 1095 Jiefang Ave, Wuhan 430030, Hubei, Peoples R China.; Chen, SY (corresponding author), Harvard Med Sch, BIDMC, CLS-432,330 Brookline Ave, Boston, MA 02215 USA."

来源：MOLECULAR ONCOLOGY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000646421700001

JCR分区：Q1

影响因子：6.6

年份：2021

卷号：15

期号：7

开始页：1901

结束页：1920

文献类型：Article

关键词：androgen receptor; CDK1; CDK9; ChIP‐ Seq; enhancer‐ promoter loop; serine 81 phosphorylation

摘要："Androgen receptor (AR) is the principal molecule in prostate cancer (PCa) etiology and therapy. AR re-activation still remains a major challenge during treatment of castration-resistant prostate cancer (CRPC) tumors that relapse after castration therapies. Recent reports have indicated the enrichment of Ser81-phosphorylated AR (pS81) in the nucleus of CRPC cells, and CDK1 and CDK9 as the kinases phosphorylating AR at S81. In the current study we showed that pS81 is preferentially localized in the nucleus in both rapid biopsy metastatic CRPC samples and PCa xenografts, and nuclear pS81 localization is correlated with AR transactivation in tumor xenografts. Chromatin immunoprecipitation (ChIP) analysis demonstrated an alignment of S81 phosphorylation and AR-mediated transactivation with the chromatin locus openness. Moreover, pS81-specific ChIP-Seq showed a disproportional occupancy of pS81 on AR-activated promoters, while 3C-ChIP assays further indicated an enrichment of pS81 at the PSA enhancer-promoter loop, a known AR activating hub. In the latter, CDK9 was shown to modulate the transactivation of the AR and RNA Pol II. Indeed, ChIP and re-ChIP assays also confirmed that AR-dependent activation of the PSA enhancer and promoter mediated by pS81 was coupled with activation of Pol II and the pTEFb complex. Mechanistically, we determined that CDK1 and CDK9 sustained the pS81 AR modification in the soluble and chromatin-bound fractions of PCa cells, respectively. Finally, we demonstrated that CDK1 activity was maintained throughout the cell cycle, and that CDK1 inhibitors restored androgen sensitivity in CRPC tumor cells. Based on these findings, CDK1 and CDK9 could be targeted as pS81 kinases in patients with CRPC, either alone or in conjunction with direct AR antagonists."

基金机构："National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81702518, 81502224]; Huazhong University of Science and Technology [2019kfyXKJC06]; Wuhan Medicine Talented Youth Development Foundation [2018-116]; NIH K99/R00 grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA135592]; DODUnited States Department of Defense [W81XWH-14-1-0016]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA163227]"

基金资助正文："This work is supported by grants from National Natural Science Foundation of China (Grant Number: 81702518, to XML), Huazhong University of Science and Technology (Grant Number: 2019kfyXKJC06, to XML), National Natural Science Foundation of China (Grant number 81502224, to JQL), Wuhan Medicine Talented Youth Development Foundation (Grant number 2018-116, to JQL), NIH K99/R00 grant (CA135592, to SC) DOD grant (W81XWH-14-1-0016, to SC), and NIH P01 (CA163227). We thank Professor Steven P. Balk for support and Drs Mannan Nouri, Larysa Poluben and Yiming Wu (BIDMC, Harvard Medical School, Boston, MA, USA) for help in the preparation of this report."