| Literature DB >> 25822367 |
Rohit Malik1, Amjad P Khan1, Irfan A Asangani1, Marcin Cieślik1, John R Prensner1, Xiaoju Wang1, Matthew K Iyer1, Xia Jiang1, Dmitry Borkin2, June Escara-Wilke1, Rachell Stender1, Yi-Mi Wu1, Yashar S Niknafs3, Xiaojun Jing1, Yuanyuan Qiao1, Nallasivam Palanisamy4, Lakshmi P Kunju5, Pranathi M Krishnamurthy3, Anastasia K Yocum3, Dattatreya Mellacheruvu6, Alexey I Nesvizhskii7, Xuhong Cao8, Saravana M Dhanasekaran1, Felix Y Feng9, Jolanta Grembecka2, Tomasz Cierpicki2, Arul M Chinnaiyan10.
Abstract
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.Entities:
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Year: 2015 PMID： 25822367 PMCID： PMC4390530 DOI： 10.1038/nm.3830
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440