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 language | English (US) |
---|---|
Pages (from-to) | E4179-E4188 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 115 |
Issue number | 18 |
DOIs | |
State | Published - May 1 2018 |
Keywords
- Castration resistance
- LSD1
- Prostate cancer
- ZNF217
ASJC Scopus subject areas
- General