Abstract Lysine-specific demethylase 1A (LSD1) is a chromatin-modifying enzyme that demethylates active chromatin marks, mono- and dimethylated H3K4, leading to gene repression. Our previous studies demonstrated that LSD1 can also demethylate the lineage-defining pioneer transcription factors FOXA1 and FOXA2, thereby stabilizing their chromatin binding and enhancing enhancer activation. In luminal-type prostate cancer, LSD1 acts as a key co-regulator with AR and FOXA1 to maintain luminal identity. Recent reports suggest that LSD1 also plays a critical role in neuroendocrine prostate cancer (NEPC) ; however, the underlying mechanisms remain poorly understood. LSD1 has a neuron-specific splice isoform, LSD1+8a, which has been reported to be exclusively expressed in NEPC and proposed as a potential biomarker. Yet, whether LSD1+8a functionally contributes to NEPC development remains unclear. Using murine prostate cancer models with lineage plasticity, including SKO (Pten loss), DKO (Pten/Rb loss), and TKO (Pten/Rb/Trp53 loss), we detected high endogenous expression of LSD1+8a mRNA and protein in DKO and TKO models (accounting for ∼5–10% of total LSD1 transcripts), but markedly lower levels in SKO tumors. In the DKO model, siRNA-mediated specific silencing of LSD1+8a significantly inhibited cell proliferation and migration compared to total LSD1 knockdown. LSD1+8a depletion also more effectively reduced expression of neuroendocrine markers (CHGA, ENO2) and key transcriptional drivers (FOXA2, MYC), suggesting a functional role in maintaining the NE phenotype. To further define its function, we generated doxycycline-inducible PC-3 stable lines overexpressing either LSD1+8a or wild-type (WT) LSD1. Overexpression of LSD1+8a, but not WT LSD1, drove PC-3 cells toward a neuroendocrine-like phenotype. Mechanistically, LSD1+8a exhibited weaker interaction with the canonical neuronal repressor CoREST complex but showed enhanced interaction with FOXA2. Ongoing studies are examining the differential chromatin occupancy and transcriptional programs regulated by LSD1+8a. Our findings identify LSD1+8a as a functionally critical isoform that promotes NEPC progression, possibly through enhanced interaction with FOXA2 or other NE driver transcription factors. Targeting this neuron-specific isoform may offer a novel therapeutic strategy to combat NEPC and limit lineage plasticity–driven resistance in advanced prostate cancer. Citation Format: Jaeweon Jeong, Songqi Zhang, HyeonYeong Sun, Zifeng Wang, Mingyu Liu, Yaozong Su, Shuai Gao, Changmeng Cai. The neuron-specific LSD1+8a isoform promotes neuroendocrine differentiation and lineage plasticity in prostate cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr A026.
Jeong et al. (Tue,) studied this question.