LSD1 activates a lethal prostate cancer gene network independently of its demethylase function

Archana Sehrawat, Lina Gao, Yuliang Wang, Armand Bankhead, Shannon McWeeney, Carly J. King, Jacob Schwartzman, Joshua Urrutia, William H. Bisson, Daniel J. Coleman, Sunil K. Joshi, Dae Hwan Kim, David A. Sampson, Sheila Weinmann, Bhaskar V.S. Kallakury, Deborah L. Berry, Reina Haque, Stephen K. Van Den Eeden, Sunil Sharma, Jared BearssTomasz (Tom) Beer, George Thomas, Laura Heiser, Joshi Alumkal

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E4179-E4188
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number18
DOIs
StatePublished - May 1 2018

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Gene Regulatory Networks
Neoplasm Genes
Lysine
Prostatic Neoplasms
Castration
Androgen Receptors
Histone Demethylases
Regulator Genes
Cell Survival
Carrier Proteins
Gene Expression
Neoplasms

Keywords

  • Castration resistance
  • LSD1
  • Prostate cancer
  • ZNF217

ASJC Scopus subject areas

  • General

Cite this

LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. / Sehrawat, Archana; Gao, Lina; Wang, Yuliang; Bankhead, Armand; McWeeney, Shannon; King, Carly J.; Schwartzman, Jacob; Urrutia, Joshua; Bisson, William H.; Coleman, Daniel J.; Joshi, Sunil K.; Kim, Dae Hwan; Sampson, David A.; Weinmann, Sheila; Kallakury, Bhaskar V.S.; Berry, Deborah L.; Haque, Reina; Van Den Eeden, Stephen K.; Sharma, Sunil; Bearss, Jared; Beer, Tomasz (Tom); Thomas, George; Heiser, Laura; Alumkal, Joshi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 18, 01.05.2018, p. E4179-E4188.

Research output: Contribution to journalArticle

Sehrawat, A, Gao, L, Wang, Y, Bankhead, A, McWeeney, S, 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, Beer, TT, Thomas, G, Heiser, L & Alumkal, J 2018, 'LSD1 activates a lethal prostate cancer gene network independently of its demethylase function', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 18, pp. E4179-E4188. https://doi.org/10.1073/pnas.1719168115
Sehrawat, Archana ; Gao, Lina ; Wang, Yuliang ; Bankhead, Armand ; McWeeney, Shannon ; King, Carly J. ; Schwartzman, Jacob ; Urrutia, Joshua ; Bisson, William H. ; Coleman, Daniel J. ; Joshi, Sunil K. ; Kim, Dae Hwan ; Sampson, David A. ; Weinmann, Sheila ; Kallakury, Bhaskar V.S. ; Berry, Deborah L. ; Haque, Reina ; Van Den Eeden, Stephen K. ; Sharma, Sunil ; Bearss, Jared ; Beer, Tomasz (Tom) ; Thomas, George ; Heiser, Laura ; Alumkal, Joshi. / LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 18. pp. E4179-E4188.
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AU - Schwartzman, Jacob

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AU - Bisson, William H.

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AU - Kim, Dae Hwan

AU - Sampson, David A.

AU - Weinmann, Sheila

AU - Kallakury, Bhaskar V.S.

AU - Berry, Deborah L.

AU - Haque, Reina

AU - Van Den Eeden, Stephen K.

AU - Sharma, Sunil

AU - Bearss, Jared

AU - Beer, Tomasz (Tom)

AU - Thomas, George

AU - Heiser, Laura

AU - Alumkal, Joshi

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N2 - 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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