Abstract 2737: Enhancing the efficacy of DNA methyltransferase inhibitors in colon cancer through dual targeting of EZH1 and EZH2

Abstract DNA methyltransferase inhibitors (DNMTis) have shown limited success in solid tumors, despite the prevalence of aberrant DNA methylation and associated tumor suppressor gene silencing. Colon cancer cells exposed to DNMTi accumulate lysine 27 tri-methylation on histone H3 (H3K27me3), and we and others have proposed this EZH2-dependent repressive histone modification limits DNMTi therapeutic potential. Recently we demonstrated that low-dose DNMTi treatment, which mimics solid tumor exposure in patients, sensitizes colon cancer cells to EZH2 inhibitors (EZH2is) and synergistically upregulates tumor suppressor genes and transposable elements (TEs). Importantly, the observed synergy varies among EZH2 inhibitors. Molecules targeting both EZH2 and its interchangeable catalytic counterpart, EZH1, demonstrate superior efficacy in tumor suppressor gene activation and cancer cell growth inhibition. In this study, we profiled the epigenomic landscapes that result from combination therapy with DNMTi and EZH1/2i to understand how these compounds alter the transcriptional states of solid tumors. We show that dual EZH1/2i reduces all states of H3K27 methylation (me1/me2/me3), providing additional substrates for p300/CBP deposition of H3K27 acetylation (H3K27ac) and enhancing transcriptional outcomes. Furthermore, H3K27ac is required for tumor suppressor gene activation observed with combination DNMTi and EZH1/2i treatment. These results underscore the therapeutic promise of combining DNMTi with dual EZH1/2i to reprogram the epigenetic landscape, restore tumor suppressor gene activity, and enhance the efficacy of epigenetic therapies in solid tumor treatment. Citation Format: Rochelle Tiedemann, Alison Chomiak, Ashley Wiseman, Yanqing Liu, Scott Rothbart. Enhancing the efficacy of DNA methyltransferase inhibitors in colon cancer through dual targeting of EZH1 and EZH2 [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 2737.