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.
journal_name
Proc Natl Acad Sci U S Aauthors
Sehrawat A,Gao L,Wang Y,Bankhead A 3rd,McWeeney SK,King CJ,Schwartzman J,Urrutia J,Bisson WH,Coleman DJ,Joshi SK,Kim DH,Sampson DA,Weinmann S,Kallakury BVS,Berry DL,Haque R,Van Den Eeden SK,Sharma S,Bearss J,Beerdoi
10.1073/pnas.1719168115subject
Has Abstractpub_date
2018-05-01 00:00:00pages
E4179-E4188issue
18eissn
0027-8424issn
1091-6490pii
1719168115journal_volume
115pub_type
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