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Edited by Owen N. Witte, University of California, Los Angeles, CA, and approved February 11, 2018 (received for review November 3, 2017)
Significance
Medical castration or interference with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, progression is universal, and therapies following the emergence of castration resistance do not offer durable control of the disease. Lysine-specific demethylase 1 (LSD1) is an important regulator of gene expression, including in cancer. Here, we show that LSD1 is highly expressed in tumors of patients with lethal castration-resistant prostate cancer (CRPC) and that LSD1 promotes AR-independent survival in CRPC cells in a noncanonical, demethylase-independent manner. We determined that the drug SP-2509 acts as an allosteric inhibitor of LSD1–blocking demethylase-independent functions. Our demonstration of tumor suppression with this inhibitor in CRPC preclinical models provides the rationale for clinical trials with LSD1 inhibitors.
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.
Footnotes
- ↵1To whom correspondence should be addressed. Email: alumkalj{at}ohsu.edu.
Author contributions: A.S., L.G., and J.J.A. designed research; A.S., L.G., J.S., J.U., D.J.C., S.K.J., D.-H.K., D.A.S., S.W., D.L.B., J.B., and G.V.T. performed research; R.H., S.K.V.D.E., and T.M.B. contributed new reagents/analytic tools; A.S., L.G., Y.W., A.B., S.K.M., C.J.K., W.H.B., S.W., B.V.S.K., S.S., G.V.T., L.M.H., and J.J.A. analyzed data; and A.S. and J.J.A. wrote the paper.
Conflict of interest statement: S.S. and T.M.B. have an equity interest in Salarius Pharmaceuticals, which developed SP-2509. Salarius Pharmaceuticals had no role in the design or conduct of this study.
This article is a PNAS Direct Submission.
Data deposition: Microarray data for microarray sample preparation and expression analysis have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database (accession no. GSE61630). Sequence data for RNA-seq library preparation and expression analysis have been deposited in the GEO database (accession no. GSE59009). ChIP-seq data have been deposited in the GEO database (accession no. GSE77762.)
See Commentary on page 4530.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1719168115/-/DCSupplemental.
Published under the PNAS license.
LSD1 activates a lethal prostate cancer gene network independently of its demethylase function
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