Browsing by Author "Topper, Michael J."

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    Select EZH2 inhibitors enhance viral mimicry effects of DNMT inhibition through a mechanism involving NFAT:AP-1 signaling
    (American Association for the Advancement of Science, 2024) Chomiak, Alison A.; Tiedemann, Rochelle L.; Liu, Yanqing; Kong, Xiangqian; Cui, Ying; Wiseman, Ashley K.; Thurlow, Kate E.; Cornett, Evan M.; Topper, Michael J.; Baylin, Stephen B.; Rothbart, Scott B.; Biochemistry and Molecular Biology, School of Medicine
    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.
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    ZNFX1 is a Novel Master Regulator in Epigenetically-induced Pathogen Mimicry and Inflammasome Signaling in Cancer
    (bioRxiv, 2024-10-21) Stojanovic, Lora; Abbotts, Rachel; Tripathi, Kaushlendra; Coon, Collin M.; Rajendran, Saranya; Farid, Elnaz Abbasi; Hostetter, Galen; Guarnieri, Joseph W.; Wallace, Douglas C.; Liu, Sheng; Wan, Jun; Calendo, Gennaro; Marker, Rebecca; Gohari, Zahra; Inayatullah, Mohammed M. A.; Tiwari, Vijay K.; Kader, Tanjina; Santagata, Sandro; Drapkin, Ronny; Kommoss, Stefan; Pfisterer, Jacobus; Konecny, Gottfried E.; Coopergard, Ryan; Issa, Jean-Pierre; Winterhoff, Boris J. N.; Topper, Michael J.; Sandusky, George E.; Miller, Kathy D.; Baylin, Stephen B.; Nephew, Kenneth P.; Rassool, Feyruz V.; Medical and Molecular Genetics, School of Medicine
    DNA methyltransferase and poly(ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon (IFN) genes (STING)-dependent pathogen mimicry response (PMR) in ovarian (OC) and other cancers. We now show that combining DNMTis and PARPis upregulates expression of a little-studied nucleic-acid sensor, NFX1-type zinc finger-containing 1 protein (ZNFX1). We demonstrate that ZNFX1 is a novel master regulator for PMR induction in mitochondria, serving as a gateway for STING-dependent PMR. In patient OC databases, high ZNFX1 expression levels correlate with advanced stage disease. ZNFX1 expression alone significantly correlates with an increase in overall survival in a phase 3 trial for therapy-resistant OC patients receiving bevacizumab in combination with chemotherapy. In correlative RNA-seq data, inflammasome signaling through ZNFX1 correlates with abnormal vasculogenesis. ZNFX1 controls PMR signaling through the mitochondria and may serve as a biomarker to facilitate offering personalized therapy in OC patients, highlighting the strong translational significance of our findings.