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

Archana Sehrawat, Lina Gao, Yuliang Wang, Armand Bankhead, Shannon K. McWeeney, Carly J. King, Jacob Schwartzman, Joshua Urrutia, William H. Bisson, Daniel J. Coleman, Sunil K. Joshi, Dae Hwan Kim, David A. Sampson, Sheila Weinmann, Bhaskar V.S. Kallakury, Deborah L. Berry, Reina Haque, Stephen K. Van Den Eeden, Sunil Sharma, Jared BearssTomasz M. Beer, George V. Thomas, Laura M. Heiser, Joshi J. Alumkal

Research output: Contribution to journalArticle

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E4179-E4188
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number18
DOIs
StatePublished - May 1 2018

Keywords

  • Castration resistance
  • LSD1
  • Prostate cancer
  • ZNF217

ASJC Scopus subject areas

  • General

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    Sehrawat, A., Gao, L., Wang, Y., Bankhead, A., McWeeney, S. K., King, C. J., Schwartzman, J., Urrutia, J., Bisson, W. H., Coleman, D. J., Joshi, S. K., Kim, D. H., Sampson, D. A., Weinmann, S., Kallakury, B. V. S., Berry, D. L., Haque, R., Van Den Eeden, S. K., Sharma, S., ... Alumkal, J. J. (2018). LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proceedings of the National Academy of Sciences of the United States of America, 115(18), E4179-E4188. https://doi.org/10.1073/pnas.1719168115