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

Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188. doi: 10.1073/pnas.1719168115. Epub 2018 Mar 26.

Abstract

Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR. Importantly, this effect is explained in part by activation of a lethal prostate cancer gene network in collaboration with LSD1's binding protein, ZNF217. Finally, that a small-molecule LSD1 inhibitor-SP-2509-blocks important demethylase-independent functions and suppresses castration-resistant prostate cancer cell viability demonstrates the potential of LSD1 inhibition in this disease.

Keywords: LSD1; ZNF217; castration resistance; prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Gene Regulatory Networks*
  • Histone Demethylases / antagonists & inhibitors
  • Histone Demethylases / genetics
  • Histone Demethylases / metabolism*
  • Humans
  • Hydrazines / pharmacology
  • Male
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / enzymology*
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Sulfonamides / pharmacology
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • Hydrazines
  • Neoplasm Proteins
  • SP2509
  • Sulfonamides
  • Trans-Activators
  • ZNF217 protein, human
  • Histone Demethylases
  • KDM1A protein, human