Lysine-specific demethylase 1 (LSD1) is a histone demethylase that promotes stemness and cell survival in cancers such as prostate cancer. Most prostate malignancies are adenocarcinomas with luminal differentiation. However, some tumors undergo cellular reprogramming to a more lethal subset termed neuroendocrine prostate cancer (NEPC) with neuronal differentiation. The frequency of NEPC is increasing since the widespread use of potent androgen receptor signaling inhibitors. Currently, there are no effective treatments for NEPC. We previously determined that LSD1 promotes survival of prostate adenocarcinoma tumors. However, the role of LSD1 in NEPC is unknown. Here, we determined that LSD1 is highly upregulated in NEPC versus adenocarcinoma patient tumors. LSD1 suppression with RNAi or allosteric LSD1 inhibitors - but not catalytic inhibitors - reduced NEPC cell survival. RNA-Seq analysis revealed that LSD1 represses pathways linked to luminal differentiation, and TP53 was the top reactivated pathway. We confirmed that LSD1 suppressed the TP53 pathway by reducing TP53 occupancy at target genes while LSD1's catalytic function was dispensable for this effect. Mechanistically, LSD1 inhibition disrupted LSD1-HDAC interactions, increasing histone acetylation at TP53 targets. Finally, LSD1 inhibition suppressed NEPC tumor growth in vivo. These findings suggest that blocking LSD1's noncatalytic function may be a promising treatment strategy for NEPC.
JCI insight. 2023 Aug 08*** epublish ***
Anbarasu Kumaraswamy, Zhi Duan, Diana Flores, Chao Zhang, Archana Sehrawat, Ya-Mei Hu, Olivia A Swaim, Eva Rodansky, William K Storck, Joshua A Kuleape, Karan Bedi, Rahul Mannan, Xiao-Ming Wang, Aaron Udager, Visweswaran Ravikumar, Armand Bankhead, Ilsa Coleman, John K Lee, Colm Morrissey, Peter S Nelson, Arul M Chinnaiyan, Arvind Rao, Zheng Xia, Joel A Yates, Joshi J Alumkal
Department of Internal Medicine and., Knight Cancer Institute and., Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA., Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA., Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Department of Urology, University of Washington, Seattle, Washington, USA.