Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 18, Pages E4179-E4188Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1719168115
Keywords
LSD1; prostate cancer; castration resistance; ZNF217
Categories
Funding
- NIH/National Cancer Institute (NCI) Grants [R01 CA178610, R01 CA100743, R01 CA169172]
- Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence/NCI Grant [P50 CA097186]
- NIH/NCI Cancer Center Support Grants [P30 CA069533-16, P30 CA051008-16]
- Oregon Clinical and Translational Research Institute Grant from the National Center for Advancing Translational Sciences, a component of the NIH [UL1TR000128]
- NIH Roadmap for Medical Research
- Department of Defense (DOD) Synergistic Idea Award [W81XWH-16-1-0597]
- Medical Research Foundation New Investigator Award
- Kuni Foundation Scholar Award
- Prostate Cancer Foundation (PCF) Young Investigator Award
- Anna Fuller Fund
- Stand Up To Cancer-PCF Prostate Dream Team Translational Cancer Research Grant - Movember Foundation [SU2C-AACR-DT0409]
- American Association for Cancer Research [7465sc]
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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.
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