Dual EZH1/2 inhibition enhances DNMT inhibitor efficacy in colon cancer through targeting H3K27me1.

ABSTRACT: Our recent work showed that low-dose DNMT inhibitor (DNMTi) treatment sensitizes colon cancer cells to EZH2 inhibitors (EZH2i), synergistically upregulating tumor suppressor genes (TSGs) and transposable elements through activation of the calcium-calcineurin-NFAT signaling pathway. A key observation was that EZH2i displayed variable sensitivities in combination therapy, which could not be explained solely by loss of lysine 27 trimethylation on histone H3 (H3K27me3), the most commonly studied EZH2 product. This led us to perform a comprehensive pharmacologic screen of Polycomb Repressive Complex 2 (PRC2) antagonists. Here, we show that compounds targeting both EZH2 and its interchangeable catalytic subunit, EZH1, achieved superior TSG re-expression when combined with DNMTi. Integrative prot

SUBMITTER: Chomiak AA 

PROVIDER: S-EPMC12458120 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature