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.

doi:10.1101/2024.10.18.618659

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bioRxiv · 10.1101/2024.10.18.618659

ZNFX1 is a Novel Master Regulator in Epigenetically-induced Pathogen Mimicry and Inflammasome Signaling in Cancer

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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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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.. 2024-10-21. ZNFX1 is a Novel Master Regulator in Epigenetically-induced Pathogen Mimicry and Inflammasome Signaling in Cancer. https://doi.org/10.1101/2024.10.18.618659

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