|Title||LSD1 activates a lethal prostate cancer gene network independently of its demethylase function.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Sehrawat, A, Gao, L, Wang, Y, Bankhead, A, McWeeney, SK, King, CJ, Schwartzman, J, Urrutia, J, Bisson, WH, Coleman, DJ, Joshi, SK, Kim, D-H, Sampson, DA, Weinmann, S, Kallakury, BVS, Berry, DL, Haque, R, Van Den Eeden, SK, Sharma, S, Bearss, J, Beer, TM, Thomas, GV, Heiser, LM, Alumkal, JJ|
|Journal||Proc Natl Acad Sci U S A|
|Date Published||2018 Mar 26|
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.
|Alternate Journal||Proc. Natl. Acad. Sci. U.S.A.|