LAUSR

ONECUT2 is a lineage plasticity driver and therapeutic target in aggressive prostate cancer (PCa). The goal of this study was to determine the role of ONECUT2 gene-body DNA methylation in regulating its expression and to evaluate its potential as a biomarker and therapeutic target for aggressive PCa. We observed a robust positive correlation between ONECUT2 expression levels and gene-body DNA methylation. This role was confirmed in prostate cancer cells through treatment with a DNA methylation inhibitor (DNMTi). Targeted bisulfite sequencing was performed to measure ONECUT2 gene-body DNA methylation in 208 needle biopsies from PCa patients, revealing a correlation between ONECUT2 gene-body hypermethylation and aggressive features. Thus, measuring ONECUT2 gene-body DNA methylation in clinical specimens can provide a predictive assessment of disease progression before surgery. Our results also suggest that downregulating ONECUT2 expression using DNMTi may be a viable therapeutic strategy for treating aggressive PCa. Citation Format: Gangning Liang, Gangning Liang. Gene-body DNA methylation of ONECUT2 predicts its expression status and prostate cancer aggressiveness in clinic specimens [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B013.