LSD1 activates a lethal prostate cancer gene network independently of its demethylase function

DOI Web Site 4 Citations
  • Archana Sehrawat
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
  • Lina Gao
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
  • Yuliang Wang
    Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239;
  • Armand Bankhead
    Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109;
  • Shannon K. McWeeney
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
  • Carly J. King
    Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239;
  • Jacob Schwartzman
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
  • Joshua Urrutia
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
  • William H. Bisson
    Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331;
  • Daniel J. Coleman
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
  • Sunil K. Joshi
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
  • Dae-Hwan Kim
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
  • David A. Sampson
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
  • Sheila Weinmann
    Center for Health Research, Kaiser Permanente NW, Portland, OR 97227;
  • Bhaskar V. S. Kallakury
    Pathology, Medstar Georgetown University Hospital, Washington, DC 20007;
  • Deborah L. Berry
    Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057;
  • Reina Haque
    Research and Evaluation, Kaiser Permanente, Pasadena, CA 91101;
  • Stephen K. Van Den Eeden
    Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612;
  • Sunil Sharma
    Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112;
  • Jared Bearss
    Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112;
  • Tomasz M. Beer
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
  • George V. Thomas
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
  • Laura M. Heiser
    Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239;
  • Joshi J. Alumkal
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;

Abstract

<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>

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