@article{d106e5e0d9164c2e82d67ff47accced3,
title = "LSD1 activates a lethal prostate cancer gene network independently of its demethylase function",
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{\textquoteright}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 = "Castration resistance, LSD1, Prostate cancer, ZNF217",
author = "Archana Sehrawat and Lina Gao and Yuliang Wang and Armand Bankhead and McWeeney, {Shannon K.} and King, {Carly J.} and Jacob Schwartzman and Joshua Urrutia and Bisson, {William H.} and Coleman, {Daniel J.} and Joshi, {Sunil K.} and Kim, {Dae Hwan} and Sampson, {David A.} and Sheila Weinmann and Kallakury, {Bhaskar V.S.} and Berry, {Deborah L.} and Reina Haque and {Van Den Eeden}, {Stephen K.} and Sunil Sharma and Jared Bearss and Beer, {Tomasz M.} and Thomas, {George V.} and Heiser, {Laura M.} and Alumkal, {Joshi J.}",
note = "Funding Information: We thank Ms. Mandy Burns and Ms. Shanta Green for help with submitting the manuscript. This research was supported by NIH/National Cancer Institute (NCI) Grants R01 CA178610, R01 CA100743, and R01 CA169172; Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence/NCI Grant P50 CA097186; NIH/NCI Cancer Center Support Grants P30 CA069533-16 and P30 CA051008-16; Oregon Clinical and Translational Research Institute Grant UL1TR000128 from the National Center for Advancing Translational Sciences, a component of the NIH and NIH Roadmap for Medical Research; and a Department of Defense (DOD) Synergistic Idea Award W81XWH-16-1-0597. Other support includes a Medical Research Foundation New Investigator Award, Kuni Foundation Scholar Award, a Prostate Cancer Foundation (PCF) Young Investigator Award, Anna Fuller Fund, and Stand Up To Cancer-PCF Prostate Dream Team Translational Cancer Research Grant SU2C-AACR-DT0409 made possible by the generous support of the Movember Foundation. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (7465sc). RNA and ChIP-sequencing were performed in the OHSU Massively Parallel Sequencing Shared Resource. Affymetrix microarrays were performed in the OHSU Gene Profiling Shared Resource. Mass spectrometry was performed in the OHSU Proteomics Shared Resource. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or DOD. Funding Information: ACKNOWLEDGMENTS. We thank Ms. Mandy Burns and Ms. Shanta Green for help with submitting the manuscript. This research was supported by NIH/National Cancer Institute (NCI) Grants R01 CA178610, R01 CA100743, and R01 CA169172; Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence/NCI Grant P50 CA097186; NIH/NCI Cancer Center Support Grants P30 CA069533-16 and P30 CA051008-16; Oregon Clinical and Translational Research Institute Grant UL1TR000128 from the National Center for Advancing Translational Sciences, a component of the NIH and NIH Roadmap for Medical Research; and a Department of Defense (DOD) Synergistic Idea Award W81XWH-16-1-0597. Other support includes a Medical Research Foundation New Investigator Award, Kuni Foundation Funding Information: Scholar Award, a Prostate Cancer Foundation (PCF) Young Investigator Award, Anna Fuller Fund, and Stand Up To Cancer-PCF Prostate Dream Team Translational Cancer Research Grant SU2C-AACR-DT0409 made possible by the generous support of the Movember Foundation. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (7465sc). RNA and ChIP-sequencing were performed in the OHSU Massively Parallel Sequencing Shared Resource. Affymetrix microarrays were performed in the OHSU Gene Profiling Shared Resource. Mass spectrometry was performed in the OHSU Proteomics Shared Resource. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or DOD. Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All rights reserved.",
year = "2018",
month = may,
day = "1",
doi = "10.1073/pnas.1719168115",
language = "English (US)",
volume = "115",
pages = "E4179--E4188",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "18",
}