Abstract 1357: The essential role of KDM5B/SOX9 signaling Axis in the development and progression of therapy-induced neuroendocrine prostate cancer.

Abstract Therapy-induced neuroendocrine prostate cancer (t-NEPC) represents a subset of lethal prostate cancer (PCa) resistant to androgen deprivation therapy (ADT). Current intervention strategies for t-NEPC are largely undefined, underscoring the urgent need to better understand its molecular mechanisms. Lysine (K)-specific demethylase 5B (KDM5B), a key epigenetic regulator, is frequently elevated in advanced PCa and t-NEPC. Similarly, the transcription factor sex-determining region Y (SRY)-box 9 (SOX9) is a critical regulator of prostate development and has been implicated in PCa. In this study, we investigated the functional role of the KDM5B/SOX9 signaling pathway on the development and progression of t-NEPC. We found that the levels of KDM5B and SOX9 are abnormally elevated in human NEPC cells. Remarkably, KDM5B depletion led to a significant reduction in mRNA and protein levels of SOX9 and neuroendocrine markers (Neuron-specific enolase and Synaptophysin) in PC3 cells. Conversely, KDM5B add-back to KDM5B knockout (KO) cells restored their levels in a dose-dependent manner. Importantly, the recurrent tumors of castrated Pten/Trp53 mice displayed the malignant features of t-NEPC, along with elevated Kdm5b and Sox9 levels. Surprisingly, Kdm5b deficiency abrogated the t-NEPC progression in Pten/Trp53/Kdm5b mutant mice, indicating the essential role of Kdm5b in t-NEPC progression in vivo. Furthermore, we observed an increase in KDM5B and SOX9 levels in LNCaP-MDV cells, a LNCaP-derived NEPC cell line. Mechanistically, KDM5B regulated SOX9 signaling in PCa cells by directly binding to the SOX9 promoter. To further elucidate the contributions of the KDM5B/SOX9 signaling axis to t-NEPC progression, we generated SOX9 KO PCa cells using CRISPR/Cas9 technology. Our results showed that SOX9 KO significantly decreased the proliferation and the levels of neuroendocrine markers in PCa cells, without impacting KDM5B levels. In conclusion, our findings in vitro and in vivo demonstrate the essential role of KDM5B/SOX9 signaling pathway in the development and progression of t-NEPC, suggesting that targeting this pathway could represent a novel and effective therapeutic strategy for controlling t-NEPC. Citation Format: Guoliang Li, Sherly Celada, Qingguo Wang, Renjie Jin, Thanigaivelan Kanagasabai, Qiujia Shao, Bindong Liu, Samuel Evans Adunyah, Paula Hurley, Zhenbang Chen. The essential role of KDM5B/SOX9 signaling Axis in the development and progression of therapy-induced neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1357.