Abstract 2982: Role of high mobility group nucleosome-binding domain-containing protein 3 (HMGN3) in prostate cancer progression a novel target for therapeutic intervention

Abstract Prostate cancer (PCa) accounts for more than one million new cases globally each year. Standard therapeutic approaches such as chemotherapy, radiotherapy, prostatectomy, and androgen deprivation therapy often yield only temporary benefits and are associated with substantial toxicity. Neuroendocrine prostate cancer (NEPC) represents a rare, highly aggressive subtype of PCa that may develop de novo or emerge as a treatment-resistant form of adenocarcinoma. NEPC is particularly challenging to manage because it is androgen receptor (AR) independent and responds poorly to conventional therapies. Chromatin modulators such as EZH2, BRD4, and NKX2-1 have been shown to promote the development of NEPC. One such novel chromatin regulator namely High Mobility Group Nucleosome-Binding Domain-Containing Protein 3 (HMGN3), a member of the HMGN protein family, binds nucleosomes and modulates chromatin structure, thereby influencing transcription, replication, and DNA repair may also have a role in the progression of NEPC. Previous research has demonstrated that HMGN3 promotes metastasis in cholangiocarcinoma by binding to the transcription factor SNAI2 and interacting with histone deacetylases (HDACs), leading to repression of epithelial-regulatory genes and induction of epithelial-mesenchymal transition (EMT). However, its role in PCa has not been previously explored. Bioinformatic analyses using PCA Tools and Betastasis indicate that AR-negative and neuroendocrine cell lines—such as NCI-H660 and LASCPC—exhibit the highest mRNA expression levels of HMGN3. This suggests that HMGN3 may contribute to EMT-associated metastatic pathways in PCa. To explore this, western blotting and RT-PCR were performed to analyze HMGN3 protein and mRNA levels in NEPC cell lines. Both NCI-H660 and LASCPC showed high protein expression, with LASCPC displaying the highest mRNA expression. Functional assays were carried out by treating BPH-1 cells with rHMGN3 in colony formation assays (CFA), while TRAMP-C1 cells were used for wound healing and Transwell migration assays. In these assays, treated groups demonstrated increased colony formation, accelerated wound closure, and higher migratory activity compared to controls. Additionally, a preliminary MTT cell viability assay performed in NCI-H660 cells treated with varying concentrations of monoclonal antibody targeted to HMGN3 showed reduced cell viability relative to untreated controls. Collectively, these findings suggest that HMGN3 as a significant enhancer of tumor growth and metastatic spread, being especially abundantly expressed in aggressive NEPC. In conclusion, our data supports that targeting HMGN3 could serve as an innovative therapeutic approach for advanced, treatment-resistant forms of PCa. Citation Format: Vikkram Venkatesan, Jeffrey Mathew, Janani Harikrishnan, Gnanasekar Munirathinam. Role of high mobility group nucleosome-binding domain-containing protein 3 (HMGN3) in prostate cancer progression a novel target for therapeutic intervention 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 2982.