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J Yang, Dept. of Molecular Biology, Chinese PLA General Hospital, Beijing, China
Y Zhao, Dept. of Molecular Biology, Chinese PLA General Hospital, Beijing, China
Z Wu, Dept. of Molecular Biology, Chinese PLA General Hospital, Beijing, China
Y Si, Dept. of Molecular Biology, Chinese PLA General Hospital, Beijing, China
Y Meng, Dept. of Molecular Biology, Chinese PLA General Hospital, Beijing, China
X Fu, Dept. of Molecular Biology, Chinese PLA General Hospital, Beijing, China
Y Mu, Department of Endocrinology, Chinese PLA General Hospital, Beijing, China
W Han, Dept. of Molecular Biology, Chinese PLA General Hospital, Beijing, 100853, China

Correspondence: Weidong Han, Email: hanwdrsw69{at}yahoo.com

Abstract

LRP16 is a special member of the macro domain superfamily, containing only a stand-alone macro domain functional module. Previous study demonstrated that the estrogenically regulated LRP16 cooperates with the estrogen receptorand enhances the receptor’s transcriptional activity in an estrogen-dependent manner. Here, we discovered that LRP16 binds to androgen receptor (AR) via its macro domain and amplifies the transactivation function of AR in response to androgen. Similarly, we also discovered that LRP16 acts as a potential coactivator to amplify the transactivation of at least other four nuclear receptors (NRs). Importantly, we show that the single macro domain in LRP16 can serve as the AR coactivator. RNA interference knockdown of LRP16 leads to impaired AR function and greatly attenuates the coactivation of AR by other AR coactivators such as ART-27 and SRC-1. This interference also markedly inhibits the androgen-stimulated proliferation of androgen-sensitive LNCaP prostate cancer cells. However, LRP16 knockdown did not significantly affect the growth rate of AR-negative PC-3 prostate cancer cells. Furthermore, we observed the induction effect of LRP16 expression by androgen and established a feed-forward mechanism that activated AR transactivation. Our results suggest that the macro domain protein LRP16 represents a novel type of cofactor of nuclear receptors. They also indicate that LRP16 plays an essential role in AR transactivation.