Dissecting transcription of the 8q24-MYC locus in prostate cancer recognizes the equilibration between androgen receptor direct and indirect dual-functions

作者全名："Guo, Ju; Wei, Zhao; Jia, Tianwei; Wang, Liyang; Nama, Nuosu; Liang, Jiaqian; Liao, Xinghua; Liu, Xiaming; Gao, Yanfei; Liu, Xiaoqiang; Wang, Keshan; Fu, Bin; Chen, Shaoyong Shawn"

作者地址："[Guo, Ju; Liu, Xiaoqiang; Fu, Bin; Chen, Shaoyong Shawn] Nanchang Univ, Dept Urol, Affiliated Hosp 1, Yongwai St 17, Nanchang 330006, Peoples R China; [Wei, Zhao] Shandong Univ, Dept Clin Lab, Qilu Hosp, Jinan 250012, Shandong, Peoples R China; [Jia, Tianwei] Shandong Univ, Hosp 2, Cheeloo Coll Med, Dept Clin Lab, Jinan 250033, Shandong, Peoples R China; [Jia, Tianwei] Shandong Engn & Technol Res Ctr Tumor Marker Detec, Jinan 250033, Shandong, Peoples R China; [Jia, Tianwei] Shandong Prov Clin Med Res Ctr, Clin Lab, Jinan 250033, Shandong, Peoples R China; [Wang, Liyang; Nama, Nuosu; Wang, Keshan; Chen, Shaoyong Shawn] Beth Israel Deaconess Med Ctr, Dept Med, Hematol Oncol Div, Boston, MA 02215 USA; [Wang, Liyang; Nama, Nuosu; Wang, Keshan; Chen, Shaoyong Shawn] Harvard Med Sch, Boston, MA 02215 USA; [Wang, Liyang] Shaanxi Normal Univ, Coll Life Sci, Dept Cell & Dev Biol, Xian 710119, Shanxi, Peoples R China; [Nama, Nuosu] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 North Wolfe St, Baltimore, MD 21205 USA; [Liang, Jiaqian] Wuhan 1 Hosp, Dept Urol, 215 Zhongshan Ave, Wuhan, Peoples R China; [Liao, Xinghua] Wuhan Univ Sci & Technol, Coll Life & Hlth Sci, Inst Biol & Med, 947 Heping Ave, Wuhan 430081, Hubei, Peoples R China; [Liu, Xiaming] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Urol, 1095 Jiefang Ave, Wuhan 430030, Hubei, Peoples R China; [Gao, Yanfei] Chongqing Med Univ, Ctr Med Epigenet, Sch Basic Med Sci, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China; [Wang, Keshan] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Urol, 1277 Jiefang Ave, Wuhan 430022, Peoples R China; [Wang, Keshan] Huazhong Univ Sci & Technol, Union Hosp, Inst Urol, Tongji Med Coll, 1277 Jiefang Ave, Wuhan 430022, Peoples R China"

通信作者："Fu, B; Chen, SS (通讯作者)，Nanchang Univ, Dept Urol, Affiliated Hosp 1, Yongwai St 17, Nanchang 330006, Peoples R China.; Wang, KS; Chen, SS (通讯作者)，Beth Israel Deaconess Med Ctr, Dept Med, Hematol Oncol Div, Boston, MA 02215 USA.; Wang, KS; Chen, SS (通讯作者)，Harvard Med Sch, Boston, MA 02215 USA.; Wang, KS (通讯作者)，Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Urol, 1277 Jiefang Ave, Wuhan 430022, Peoples R China.; Wang, KS (通讯作者)，Huazhong Univ Sci & Technol, Union Hosp, Inst Urol, Tongji Med Coll, 1277 Jiefang Ave, Wuhan 430022, Peoples R China."

来源：JOURNAL OF TRANSLATIONAL MEDICINE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001099703800003

JCR分区：Q1

影响因子：7.4

年份：2023

卷号：21

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Androgen receptor; Transcriptional dual-functions; 8q24-MYC locus; AR binding sites; CRIPSR/Cas9 genomic knock-out; Co-factor redistribution; Prostate cancer

摘要："Background Androgen receptor (AR) activation and repression dual-functionality only became known recently and still remains intriguing in prostate cancer (PCa). MYC is a prominent oncogene that functionally entangles with AR signaling in PCa. Further exploration of AR regulatory mechanisms on MYC gene transcription bears clinical and translation significance. Methods Bioinformatics analysis of PCa cell line and clinical RNA-Seq and ChIP-Seq (chromatin immunoprecipitation-sequencing) datasets to anchor interactions of AR and MYC transcriptional networks. ChIP-qPCR and 3C (chromosome conformation capture) analyses to probe MYC distal regulation by AR binding sites (ABSs). CRISPR/Cas9-mediated genome-editing to specify functions of ABS within the 8q24-MYC locus on androgen-mediated MYC transcription. Global FoxA1 and HoxB13 distribution profiling to advance AR transcriptional mechanisms. Results Here we recognize AR bi-directional transcription mechanisms by exploiting the prominent 8q24-MYC locus conferring androgen hyper-sensitivity. At similar to 25 Kb downstream of the MYC gene, we identified an undefined ABS, P10. By chromatin analyses, we validated androgen-dependent spatial interaction between P10 and MYC-Promoter (MYC-Pro) and temporal epigenetic repression of these MYC-proximal elements. We next designed a CRISPR/Cas9-mediated double genomic knock-out (KO) strategy to show that P10-KO slightly lessened androgen-elicited MYC transrepression in LNCaP-AR cells. In similar genomic editing assays, androgen-mediated MYC repression became slightly deepened upon KO of P11, an ABS in the PVT1 gene locus highly enriched in AR-binding motifs and peaks. We also investigated multiple ABSs in the established PCAT1 super-enhancer that distally interacts with MYC-Pro for transactivation, with each KO pool consistently shown to relieve androgen-elicited MYC repression. In the end, we systemically assessed androgen effects in the 8q24-MYC locus and along PCa genome to generalize H3K27ac and BRD4 re-distribution from pioneer factors (FoxA1 and HoxB13) to AR sites. Conclusion Together, we reconciled these observations by unifying AR dual-functions that are mechanistically coupled to and equilibrated by co-factor redistribution. [GRAPHICS] ."

基金机构："This work is supported by the following grants: general projects of key Ramp;D projects in Jiangxi Province, P.R. China (20203BBGL73180 to JG); the Natural Science Foundation of Shandong Province, P.R. China (ZR2019PH021 to ZW); the National Natural Scien [20203BBGL73180]; general projects of key Ramp;D projects in Jiangxi Province, P.R. China [ZR2019PH021]; Natural Science Foundation of Shandong Province, P.R. China [32170578]; National Natural Science Foundation, P.R. China [2021fzyx019]; Foundation of Hubei Province Key Laboratory of Molecular Imaging, P.R. China [CA135592]; NIH K99/R00 grant, USA [W81XWH-14-1-0016]; DOD grant, USA"

基金资助正文："This work is supported by the following grants: general projects of key R&D projects in Jiangxi Province, P.R. China (20203BBGL73180 to JG); the Natural Science Foundation of Shandong Province, P.R. China (ZR2019PH021 to ZW); the National Natural Science Foundation, P.R. China (81901421 to ZW); Foundation of Hubei Province Key Laboratory of Molecular Imaging, P.R. China (2021fzyx019 to KSW); the National Natural Science Foundation, P.R. China (Grant No. 81960512 to BF); NIH K99/R00 grant, USA (CA135592 to SSC); DOD grant, USA (W81XWH-14-1-0016, to SSC); and the National Natural Science Foundation, P.R. China (32170578 to SSC)."