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

Autor:	Stojanovic L; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA.; Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Abbotts R; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA.; Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Tripathi K; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA.; Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Coon CM; Medical Sciences Program, Indiana University School of Medicine-Bloomington, Bloomington, IN 47405, USA., Rajendran S; Medical Sciences Program, Indiana University School of Medicine-Bloomington, Bloomington, IN 47405, USA., Farid EA; Medical Sciences Program, Indiana University School of Medicine-Bloomington, Bloomington, IN 47405, USA., Hostetter G; Van Andel Research Institute, Grand Rapids, MI 49503, USA., Guarnieri JW; Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Wallace DC; Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Pediatrics, Division of Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Liu S; Department of Medical and Molecular Genetics, Indiana University School of Medicine Indianapolis, IN 46202, USA.; Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine Indianapolis, IN 46202, USA., Wan J; Department of Medical and Molecular Genetics, Indiana University School of Medicine Indianapolis, IN 46202, USA.; Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine Indianapolis, IN 46202, USA., Calendo G; Coriell Institute for Medical Research, Camden, NJ 08103., Marker R; Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Gohari Z; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA.; Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Inayatullah MMA; University of Southern Denmark, Odense, Denmark., Tiwari VK; University of Southern Denmark, Odense, Denmark., Kader T; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.; Ludwig Center at Harvard, Boston, MA, USA., Santagata S; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.; Ludwig Center at Harvard, Boston, MA, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Drapkin R; Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA., Kommoss S; Diakonie-Klinikum Schwäbisch Hall, Germany, Institute for Health Informatics.; Kliniken Essen-Mitte, Gynäkologie und Gynäkologische Onkologie, Germany., Pfisterer J; Department of Medicine, David Geffen School of Medicine., Konecny GE; University of California Los Angeles, Los Angeles, CA., Coopergard R; Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA., Issa JP; Coriell Institute for Medical Research, Camden, NJ 08103., Winterhoff BJN; Department of Obstetrics, Gynecology and Women's Health (OBGYN), Division of Gynecologic Oncology, University of Minnesota, MN 55812-3011, USA., Topper MJ; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA., Sandusky GE; Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA., Miller KD; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA.; Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Baylin SB; Diakonie-Klinikum Schwäbisch Hall, Germany, Institute for Health Informatics.; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA., Nephew KP; Medical Sciences Program, Indiana University School of Medicine-Bloomington, Bloomington, IN 47405, USA.; Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine Indianapolis, IN 46202, USA.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA., Rassool FV; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA.; Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 21. Date of Electronic Publication: 2024 Oct 21.
DOI:	10.1101/2024.10.18.618659
Abstrakt:	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. Competing Interests: Disclosure of Conflicts of Interest F.V.R. and S.B.B. share co-inventorship on US Provisional Patent Application Number: 61/929,680 for the concept of the combinatorial therapy. The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. All other authors declare no potential conflicts of interest.
Databáze:	MEDLINE
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