LSD1 activates a lethal prostate cancer gene network independently of its demethylase function
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- Archana Sehrawat
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
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- Lina Gao
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
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- Yuliang Wang
- Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239;
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- Armand Bankhead
- Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109;
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- Shannon K. McWeeney
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
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- Carly J. King
- Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239;
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- Jacob Schwartzman
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
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- Joshua Urrutia
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
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- William H. Bisson
- Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331;
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- Daniel J. Coleman
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
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- Sunil K. Joshi
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
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- Dae-Hwan Kim
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
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- David A. Sampson
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
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- Sheila Weinmann
- Center for Health Research, Kaiser Permanente NW, Portland, OR 97227;
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- Bhaskar V. S. Kallakury
- Pathology, Medstar Georgetown University Hospital, Washington, DC 20007;
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- Deborah L. Berry
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057;
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- Reina Haque
- Research and Evaluation, Kaiser Permanente, Pasadena, CA 91101;
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- Stephen K. Van Den Eeden
- Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612;
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- Sunil Sharma
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112;
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- Jared Bearss
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112;
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- Tomasz M. Beer
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
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- George V. Thomas
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
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- Laura M. Heiser
- Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239;
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- Joshi J. Alumkal
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
説明
<jats:title>Significance</jats:title> <jats:p>Medical castration or interference with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, progression is universal, and therapies following the emergence of castration resistance do not offer durable control of the disease. Lysine-specific demethylase 1 (LSD1) is an important regulator of gene expression, including in cancer. Here, we show that LSD1 is highly expressed in tumors of patients with lethal castration-resistant prostate cancer (CRPC) and that LSD1 promotes AR-independent survival in CRPC cells in a noncanonical, demethylase-independent manner. We determined that the drug SP-2509 acts as an allosteric inhibitor of LSD1–blocking demethylase-independent functions. Our demonstration of tumor suppression with this inhibitor in CRPC preclinical models provides the rationale for clinical trials with LSD1 inhibitors.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 115 (18), E4179-, 2018-03-26
Proceedings of the National Academy of Sciences