Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2

被引:11
作者
Labaf, Maryam [1 ,2 ]
Li, Muqing [1 ,3 ]
Ting, Lily [1 ,3 ]
Karno, Breelyn [4 ]
Zhang, Songqi [1 ,3 ]
Gao, Shuai [5 ,6 ]
Patalano, Susan [1 ,3 ]
Macoska, Jill A. A. [1 ,3 ]
Zarringhalam, Kourosh [2 ]
Han, Dong [1 ,3 ]
Cai, Changmeng [1 ,3 ]
机构
[1] Univ Massachusetts Boston, Ctr Personalized Canc Therapy, Boston, MA 02125 USA
[2] Univ Massachusetts Boston, Dept Math, Boston, MA USA
[3] Univ Massachusetts Boston, Dept Biol, Boston, MA 02125 USA
[4] Vanderbilt Univ, Dept Med, Nashville, TN USA
[5] New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY USA
[6] New York Med Coll, Dept Biochem & Mol Biol, Valhalla, NY USA
关键词
androgen; androgen receptor; AR; prostate cancer; androgen-deprivation therapy; CRPC; EZH2; DNA damage repair; ANDROGEN-RECEPTOR; INCREASED SURVIVAL; OPEN-LABEL; TRANSCRIPTION; POLYCOMB; TAZEMETOSTAT; RECRUITMENT;
D O I
10.3389/fonc.2022.1021845
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Elevated androgen receptor (AR) expression is a hallmark of castration-resistant prostate cancer (CRPC) and contributes to the restoration of AR signaling under the conditions of androgen deprivation. However, whether overexpressed AR alone with the stimulation of castrate levels of androgens can be sufficient to induce the reprogramming of AR signaling for the adaptation of prostate cancer (PCa) cells remains unclear. In this study, we used a PCa model with inducible overexpression of AR to examine the acute effects of AR overexpression on its cistrome and transcriptome. Our results show that overexpression of AR alone in conjunction with lower androgen levels can rapidly redistribute AR chromatin binding and activates a distinct transcription program that is enriched for DNA damage repair pathways. Moreover, using a recently developed bioinformatic tool, we predicted the involvement of EZH2 in this AR reprogramming and subsequently identified a subset of AR/EZH2 co-targeting genes, which are overexpressed in CRPC and associated with worse patient outcomes. Mechanistically, we found that AR-EZH2 interaction is impaired by the pre-castration level of androgens but can be recovered by the post-castration level of androgens. Overall, our study provides new molecular insights into AR signaling reprogramming with the engagement of specific epigenetic factors.
引用
收藏
页数:13
相关论文
共 48 条
[1]   Genomic correlates of clinical outcome in advanced prostate cancer [J].
Abida, Wassim ;
Cyrta, Joanna ;
Heller, Glenn ;
Prandi, Davide ;
Armenia, Joshua ;
Coleman, Ilsa ;
Cieslik, Marcin ;
Benelli, Matteo ;
Robinson, Dan ;
Van Allen, Eliezer M. ;
Sboner, Andrea ;
Fedrizzi, Tarcisio ;
Mosquera, Juan Miguel ;
Robinson, Brian D. ;
De Sarkar, Navonil ;
Kunju, Lakshmi P. ;
Tomlins, Scott ;
Wu, Yi Mi ;
Rodrigues, Daniel Nava ;
Loda, Massimo ;
Gopalan, Anuradha ;
Reuter, Victor E. ;
Pritchard, Colin C. ;
Mateo, Joaquin ;
Bianchini, Diletta ;
Miranda, Susana ;
Carreira, Suzanne ;
Rescigno, Pasquale ;
Filipenko, Julie ;
Vinson, Jacob ;
Montgomery, Robert B. ;
Beltran, Himisha ;
Heath, Elisabeth I. ;
Scher, Howard I. ;
Kantoff, Philip W. ;
Taplin, Mary-Ellen ;
Schultz, Nikolaus ;
deBono, Johann S. ;
Demichelis, Francesca ;
Nelson, Peter S. ;
Rubin, Mark A. ;
Chinnaiyan, Arul M. ;
Sawyers, Charles L. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2019, 116 (23) :11428-11436
[2]   Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer [J].
Asangani, Irfan A. ;
Dommeti, Vijaya L. ;
Wang, Xiaoju ;
Malik, Rohit ;
Cieslik, Marcin ;
Yang, Rendong ;
Escara-Wilke, June ;
Wilder-Romans, Kari ;
Dhanireddy, Sudheer ;
Engelke, Carl ;
Iyer, Mathew K. ;
Jing, Xiaojun ;
Wu, Yi-Mi ;
Cao, Xuhong ;
Qin, Zhaohui S. ;
Wang, Shaomeng ;
Feng, Felix Y. ;
Chinnaiyan, Arul M. .
NATURE, 2014, 510 (7504) :278-+
[3]   Inter- and intra-tumor heterogeneity of metastatic prostate cancer determined by digital spatial gene expression profiling [J].
Brady, Lauren ;
Kriner, Michelle ;
Coleman, Ilsa ;
Morrissey, Colm ;
Roudier, Martine ;
True, Lawrence D. ;
Gulati, Roman ;
Plymate, Stephen R. ;
Zhou, Zoey ;
Birditt, Brian ;
Meredith, Rhonda ;
Geiss, Gary ;
Hoang, Margaret ;
Beechem, Joseph ;
Nelson, Peter S. .
NATURE COMMUNICATIONS, 2021, 12 (01)
[4]   Androgen receptor epigenetics [J].
Cai, Changmeng ;
Yuan, Xin ;
Balk, Steven P. .
TRANSLATIONAL ANDROLOGY AND UROLOGY, 2013, 2 (03) :148-157
[5]   Lysine-Specific Demethylase 1 Has Dual Functions as a Major Regulator of Androgen Receptor Transcriptional Activity [J].
Cai, Changmeng ;
He, Housheng Hansen ;
Gao, Shuai ;
Chen, Sen ;
Yu, Ziyang ;
Gao, Yanfei ;
Chen, Shaoyong ;
Chen, Mei Wei ;
Zhang, Jesse ;
Ahmed, Musaddeque ;
Wang, Yang ;
Metzger, Eric ;
Schuele, Roland ;
Liu, X. Shirley ;
Brown, Myles ;
Balk, Steven P. .
CELL REPORTS, 2014, 9 (05) :1618-1627
[6]   ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancer [J].
Cai, Changmeng ;
Wang, Hongyun ;
He, Housheng Hansen ;
Chen, Sen ;
He, Lingfeng ;
Ma, Fen ;
Mucci, Lorelei ;
Wang, Qianben ;
Fiore, Christopher ;
Sowalsky, Adam G. ;
Loda, Massimo ;
Liu, X. Shirley ;
Brown, Myles ;
Balk, Steven P. ;
Yuan, Xin .
JOURNAL OF CLINICAL INVESTIGATION, 2013, 123 (03) :1109-1122
[7]   Androgen Receptor Gene Expression in Prostate Cancer Is Directly Suppressed by the Androgen Receptor Through Recruitment of Lysine-Specific Demethylase 1 [J].
Cai, Changmeng ;
He, Housheng Hansen ;
Chen, Sen ;
Coleman, Ilsa ;
Wang, Hongyun ;
Fang, Zi ;
Chen, Shaoyong ;
Nelson, Peter S. ;
Liu, X. Shirley ;
Brown, Myles ;
Balk, Steven P. .
CANCER CELL, 2011, 20 (04) :457-471
[8]   ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer [J].
Cai, Ling ;
Tsai, Yi-Hsuan ;
Wang, Ping ;
Wang, Jun ;
Li, Dongxu ;
Fan, Huitao ;
Zhao, Yilin ;
Bareja, Rohan ;
Lu, Rui ;
Wilson, Elizabeth M. ;
Sboner, Andrea ;
Whang, Young E. ;
Zheng, Deyou ;
Parker, Joel S. ;
Earp, H. Shelton ;
Wang, Gang Greg .
MOLECULAR CELL, 2018, 72 (02) :341-+
[9]   ARv7 Represses Tumor-Suppressor Genes in Castration-Resistant Prostate Cancer [J].
Cato, Laura ;
de Tribolet-Hardy, Jonas ;
Lee, Irene ;
Rottenberg, Jaice T. ;
Coleman, Ilsa ;
Melchers, Diana ;
Houtman, Rene ;
Xiao, Tengfei ;
Li, Wei ;
Uo, Takuma ;
Sun, Shihua ;
Kuznik, Nane C. ;
Goeppert, Bettina ;
Ozgun, Fatma ;
van Royen, Martin E. ;
Houtsmuller, Adriaan B. ;
Vadhi, Raga ;
Rao, Prakash K. ;
Li, Lewyn ;
Balk, Steven P. ;
Den, Robert B. ;
Trock, Bruce J. ;
Karnes, R. Jeffrey ;
Jenkins, Robert B. ;
Klein, Eric A. ;
Davicioni, Elai ;
Gruhl, Friederike J. ;
Long, Henry W. ;
Liu, X. Shirley ;
Cato, Andrew C. B. ;
Lack, Nathan A. ;
Nelson, Peter S. ;
Plymate, Stephen R. ;
Groner, Anna C. ;
Brown, Myles .
CANCER CELL, 2019, 35 (03) :401-+
[10]   Molecular determinants of resistance to antiandrogen therapy [J].
Chen, CD ;
Welsbie, DS ;
Tran, C ;
Baek, SH ;
Chen, R ;
Vessella, R ;
Rosenfeld, MG ;
Sawyers, CL .
NATURE MEDICINE, 2004, 10 (01) :33-39