期刊
NATURE MEDICINE
卷 21, 期 4, 页码 344-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nm.3830
关键词
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资金
- US National Institutes of Health (NIH) Prostate Specialized Program of Research Excellence [P50CA186786]
- Early Detection Research Network [UO1 CA111275]
- Prostate Cancer Foundation
- Howard Hughes Medical Institute
- NIH R01 grant [1R01CA160467]
- Leukemia & Lymphoma Society Translational Research Program grant [6116-12]
- American Cancer Society Research Scholar grant [RSG-11-082-01-DMC]
- NIH [R01-GM-094231]
- Department of Defense postdoctoral award [W81XWH-13-1-0284]
- Prostate Cancer Foundation Young Investigator award
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castrationresistant 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.
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