Abstract 4046: Role of kaiso in androgen receptor signaling and castration resistance

Abstract Metastatic PCa patients are treated with androgen deprivation therapy (ADT) alone or ADT together with antiandrogens such as enzalutamide (Enza). ADT/Enza targets AR-expressing PCa cells; therefore, the mechanisms underlying ADT/Enza resistance involve AR genomic alterations, AR splice variants, and persistent AR signaling even under castrated conditions. Our lab recently identified Kaiso, a BTB-POZ methyl-binding transcriptional regulator, as a crucial player in AR signaling networks. However, it is known how Kaiso potentially influences progress and treatment outcomes. Firstly, we established that Kaiso expression levels increased, as well as a cytoplasmic to nuclear localization occurred during Enza treatment. Additionally, utilizing ChIP and Cut-n-Run assays we observed that Kaiso directly binds to the methylated regions within the AR promoter. Utilizing AR-specific methylation-sequencing, we further observed that CGCG-rich regions in the AR promoter can be modulated utilizing both Kaiso depleted (sh-Kaiso) and Kaiso (overexpression) OE cell lines. Furthermore, modulation of Kaiso expression levels influences both AR and PSA. RNA-seq of Kaiso OE cells demonstrate significant AR and PSA overexpression, as well as GSEA enrichments highlight that androgen receptor signaling, epithelial to mesenchymal transition, and MYC signaling as the most significant pathways. Finally, sh-Kaiso cells displayed increased sensitivity to both Enza and ABi, while Kaiso OE cell lines displayed a complete lack of response to both compounds. In summary, our findings suggest that Kaiso levels may significantly influence androgen sensitivity and highlight Kaiso as a therapeutic target to improve conventional AR-directed therapies. Citation Format: Oceane Kircha Nana, Huixian Lin, Isra Elhussin, Md. Abu Siddique, Omna Hayyat, Moray Campbell, Clayton Yates. Role of kaiso in androgen receptor signaling and castration resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4046.