TY - JOUR
T1 - Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation
AU - Hsieh, Chen Lin
AU - Fei, Teng
AU - Chen, Yiwen
AU - Li, Tiantian
AU - Gao, Yanfei
AU - Wang, Xiaodong
AU - Sun, Tong
AU - Sweeney, Christopher J.
AU - Lee, Gwo Shu Mary
AU - Chen, Shaoyong
AU - Balk, Steven P.
AU - Liu, Xiaole Shirley
AU - Brown, Myles
AU - Kantoff, Philip W.
PY - 2014/5/20
Y1 - 2014/5/20
N2 - 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 wellknown 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.
AB - 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 wellknown 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.
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U2 - 10.1073/pnas.1324151111
DO - 10.1073/pnas.1324151111
M3 - Article
C2 - 24778216
AN - SCOPUS:84901020399
SN - 0027-8424
VL - 111
SP - 7319
EP - 7324
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -