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

Author:

Chomiak Alison A.1ORCID,Tiedemann Rochelle L.1ORCID,Liu Yanqing1ORCID,Kong Xiangqian2,Cui Ying2,Wiseman Ashley K.1ORCID,Thurlow Kate E.1ORCID,Cornett Evan M.3,Topper Michael J.2,Baylin Stephen B.2ORCID,Rothbart Scott B.1ORCID

Affiliation:

1. Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.

2. Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

3. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indiana University, Indianapolis, IN 46202, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

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