Kumaraswamy Anbarasu, Mannan Rahul, Swaim Olivia A, Rodansky Eva, Wang Xiao-Ming, Udager Aaron, Mehra Rohit, Li Hui, Morrissey Colm, Corey Eva, Haffner Michael C, Nelson Peter S, Chinnaiyan Arul M, Yates Joel A, Alumkal Joshi J
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.
Neoplasia. 2025 May;63:101151. doi: 10.1016/j.neo.2025.101151. Epub 2025 Mar 14.
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.
赖氨酸特异性去甲基化酶1（LSD1）是一种组蛋白去甲基化酶，也是包括癌症在内的分化调节因子。已表明LSD1的一种神经元特异性异构体——LSD1+8a——在促进发育中的大脑神经元分化中起关键作用。我们之前确定，在具有神经元程序的侵袭性前列腺癌亚型——神经内分泌前列腺癌（NEPC）中检测到LSD1+8a转录本，但在具有腺性程序的前列腺腺癌中未检测到。然而，所检查的样本数量有限。
我们使用大量前列腺癌患者细胞系和患者来源的异种移植瘤（PDX），通过定量聚合酶链反应（qPCR）、RNA原位杂交（RNA-ISH）和蛋白质检测方法测量LSD1+8a。然后我们使用独立的患者肿瘤样本队列验证了我们的发现。
通过qPCR和RNA-ISH在每个检测的NEPC细胞系和PDX中检测到LSD1+8a mRNA表达，但在前列腺腺癌中均未检测到。我们在患者肿瘤中验证了RNA-ISH结果，证实LSD1+8a在所有NEPC肿瘤中表达，但在腺癌中均未表达。最后，我们生成了一种对LSD1+8a蛋白特异的兔单克隆抗体，并使用正常神经元组织样本确认了其特异性。然而，在NEPC肿瘤中未检测到LSD1+8a蛋白——可能是由于NEPC肿瘤中LSD1+8a mRNA水平明显低于正常神经元组织。
测量LSD1+8a mRNA是诊断NEPC的一种敏感且特异的方法，而NEPC的诊断通常具有挑战性。
