Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation.
The androgen receptor (AR) is a key factor that regulates the behavior and fate of prostate cancer cells. The AR-regulated network is activated when AR binds enhancer elements and modulates specific enhancer-promoter looping. Kallikrein-related peptidase 3 (KLK3), which codes for prostate-specific antigen (PSA), is a well-known AR-regulated gene and its upstream enhancers produce bidirectional enhancer RNAs (eRNAs), termed KLK3e. Here, we demonstrate that KLK3e facilitates the spatial interaction of the KLK3 enhancer and the KLK2 promoter and enhances long-distance KLK2 transcriptional activation. KLK3e carries the core enhancer element derived from the androgen response element III (ARE III), which is required for the interaction of AR and Mediator 1 (Med1). Furthermore, we show that KLK3e processes RNA-dependent enhancer activity depending on the integrity of core enhancer elements. The transcription of KLK3e was detectable and its expression is significantly correlated with KLK3 (R(2) = 0.6213, P < 5 × 10(-11)) and KLK2 (R(2) = 0.5893, P < 5 × 10(-10)) in human prostate tissues. Interestingly, RNAi silencing of KLK3e resulted in a modest negative effect on prostate cancer cell proliferation. Accordingly, we report that an androgen-induced eRNA scaffolds the AR-associated protein complex that modulates chromosomal architecture and selectively enhances AR-dependent gene expression.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115;
Chen-Lin
CL
Hsieh
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115;Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215;
Teng
T
Fei
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215;Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115; and.
Yiwen
Y
Chen
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115;
Tiantian
T
Li
Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215.
Yanfei
Y
Gao
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115;
Xiaodong
X
Wang
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115;
Tong
T
Sun
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115;
Christopher J
CJ
Sweeney
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115;
Gwo-Shu Mary
GS
Lee
Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215.
Shaoyong
S
Chen
Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215.
Steven P
SP
Balk
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215;Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115; and.
Xiaole Shirley
XS
Liu
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115;Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215;
Myles
M
Brown
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115; philip_kantoff@dfci.harvard.edu.
Philip W
PW
Kantoff
D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D008297:Male; D056913:Mediator Complex Subunit 1 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D034622:RNA Interference; D011944:Receptors, Androgen / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D020840:Tissue Kallikreins / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
C410798:AR protein, human; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D011944:Receptors, Androgen; C549870:KLK3 protein, human; D007610:Kallikreins; D020840:Tissue Kallikreins; D017430:Prostate-Specific Antigen
KLK3e/AR/Med1 complex; chromosomal looping