ZNFX1 is a Novel Master Regulator in Epigenetically-induced Pathogen Mimicry and Inflammasome Signaling in Cancer
Stojanovic, L.; Abbotts, R.; Tripathi, K.; Coon, C. M.; Rajendran, S.; Abbasi Farid, E.; Hostetter, G.; Guarnieri, J. W.; Wallace, D. C.; Liu, S.; Wan, J.; Calendo, G.; Marker, R.; Gohari, Z.; Inayatullah, M. M. A.; Tiwari, V. K.; Kader, T.; Santagata, S.; Drapkin, R.; Kommoss, S.; Pfisterer, J.; Konecny, G. E.; Coopergard, R.; Issa, J.-P.; Winterhoff, B. J. N.; Topper, M. J.; Sandusky, G. E.; Miller, K. D.; Baylin, S. B.; Nephew, K. P.; Rassool, F. V.
Show abstract
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. Significance statementDNA methyltransferase and poly(ADP-ribose) polymerase inhibitors upregulate expression of a novel nucleic-acid sensor, ZNFX1 that serves as a mitochondrial gateway to STING-dependent interferon/inflammasome signaling with tumor suppressor properties in ovarian cancer.
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