Lysine-specific demethylase 1 (LSD1) is a histone demethylase and regulator of differentiation, including in cancer. A neuronal-specific isoform of LSD1-LSD1+8a-has been shown to play a key role in promoting neuronal differentiation in the developing brain. We previously determined that LSD1+8a transcripts were detected in an aggressive subtype of prostate cancer harboring a neuronal program-neuroendocrine prostate cancer (NEPC)-but not in prostate adenocarcinomas harboring a glandular program. However, the number of samples examined was limited.
Using a large collection of prostate cancer patient cell lines and patient-derived xenografts (PDXs), we measured LSD1+8a using quantitative polymerase chain reaction (qPCR), RNA in situ hybridization (RNA-ISH), and protein detection methods. We then validated our findings using an independent cohort of patient tumor samples.
LSD1+8a mRNA expression was detected in every NEPC cell line and PDX examined by qPCR and RNA-ISH but in none of the prostate adenocarcinomas. We validated the RNA-ISH results in patient tumors, confirming that LSD1+8a was expressed in all NEPC tumors but in none of the adenocarcinomas. Finally, we generated a rabbit monoclonal antibody specific to LSD1+8a protein and confirmed its specificity using normal neuronal tissue samples. However, LSD1+8a protein was not detectable in NEPC tumors-likely due to the substantially lower levels of LSD1+8a mRNA in NEPC tumors vs. normal neuronal tissues.
Measuring LSD1+8a mRNA is a sensitive and specific method for the diagnosis of NEPC, which is often challenging.
Neoplasia (New York, N.Y.). 2025 Mar 14 [Epub ahead of print]
Anbarasu Kumaraswamy, Rahul Mannan, Olivia A Swaim, Eva Rodansky, Xiao-Ming Wang, Aaron Udager, Rohit Mehra, Hui Li, Colm Morrissey, Eva Corey, Michael C Haffner, Peter S Nelson, Arul M Chinnaiyan, Joel A Yates, Joshi J Alumkal
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA., Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., RevMAb Biosciences, Burlingame, CA, USA., Department of Urology, University of Washington, Seattle, WA, USA., Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, Ann Arbor, MI, USA., Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. Electronic address: .