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LSD1 Promotes Prostate Cancer Reprogramming by Repressing TP53 Signaling Independently of Its Demethylase Function

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.

Anbarasu Kumaraswamy1,2, Zhi Duan1,2, Diana Flores1,2, Chao Zhang1,2, Archana Sehrawat3, Ya-Mei Hu3,4, Olivia A Swaim1,2,5, Eva Rodansky1,2, William K Storck1,2, Joshua A Kuleape1,2, Karan Bedi2,6, Rahul Mannan7, Xiao-Ming Wang7,8, Aaron Udager7, Visweswaran Ravikumar9, Armand Bankhead III9, Ilsa Coleman10, John K Lee10, Colm Morrissey11, Peter S Nelson10, Arul M Chinnaiyan2,7,8,12,13, Arvind Rao2,9,14,15, Zheng Xia3,4, Joel A Yates1,2, Joshi J Alumkal1,2,8

  1. Department of Internal Medicine and.
  2. Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
  3. Knight Cancer Institute and.
  4. Biomedical Engineering Department, Oregon Health & Science University (OHSU), Portland, Oregon, USA.
  5. College of Literature, Science, and the Arts, and.
  6. Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
  7. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  8. Michigan Center for Translational Pathology, Ann Arbor, Michigan, USA.
  9. Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
  10. Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  11. Department of Urology, University of Washington, Seattle, Washington, USA.
  12. Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  13. Howard Hughes Medical Institute, Ann Arbor, Michigan, USA.
  14. Department of Radiation Oncology and.
  15. Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
Source: Kumaraswamy A; Duan Z; Flores D; Zhang C; Sehrawat A; Hu YM; Swaim OA; Rodansky E; Storck WK; Kuleape JA; Bedi K; Mannan R; Wang XM; Udager A; Ravikumar V Bankhead A; Coleman I; Lee JK; Morrissey C; Nelson PS; Chinnaiyan AM; Rao A; Xia Z; Yates JA; Alumkal JJ; (2023) LSD1 Promotes Prostate Cancer Reprogramming by Repressing TP53 Signaling Independently of Its Demethylase Function, JCI insight.