Select EZH2 inhibitors enhance viral mimicry effects of DNMT inhibition through a mechanism involving NFAT:AP-1 signaling

Abstract

DNA methyltransferase inhibitor (DNMTi) efficacy in solid tumors is limited. Colon cancer cells exposed to DNMTi accumulate lysine-27 trimethylation on histone H3 (H3K27me3). We propose this Enhancer of Zeste Homolog 2 (EZH2)–dependent repressive modification limits DNMTi efficacy. Here, we show that low-dose DNMTi treatment sensitizes colon cancer cells to select EZH2 inhibitors (EZH2is). Integrative epigenomic analysis reveals that DNMTi-induced H3K27me3 accumulates at genomic regions poised with EZH2. Notably, combined EZH2i and DNMTi alters the epigenomic landscape to transcriptionally up-regulate the calcium-induced nuclear factor of activated T cells (NFAT):activating protein 1 (AP-1) signaling pathway. Blocking this pathway limits transcriptional activating effects of these drugs, including transposable element and innate immune response gene expression involved in viral defense. Analysis of primary human colon cancer specimens reveals positive correlations between DNMTi-, innate immune response–, and calcium signaling–associated transcription profiles. Collectively, we show that compensatory EZH2 activity limits DNMTi efficacy in colon cancer and link NFAT:AP-1 signaling to epigenetic therapy–induced viral mimicry.

Beyond the Usual Suspects: Examining the Role of Understudied Histone Variants in Breast Cancer

“…Fortunately, unlike genetic mutations, epigenetic aberrations have the potential to be reversible, providing new therapeutic avenues for cancer cell management. Indeed, the use of epigenetic targets in combination with conventional chemotherapeutic drugs is emerging as an effective technique for increasing anticancer activity, reducing drug resistance, and bolstering the host immune response [ 216 , 217 , 218 , 219 ]. Thus, we propose a deeper exploration of histone variants, their influence on nucleosome structure, and the downstream pathways involved in dysregulating cancer-related genes, especially in cases lacking evident DNA mutations in well-established breast cancer oncogenes.…”