Supplementary Data from ZNFX1 Functions as a Master Regulator of Epigenetically Induced Pathogen Mimicry and Inflammasome Signaling in Cancer

Stojanovic, Lora; Abbotts, Rachel; Tripathi, Kaushelendra; Coon, Collin M.; Rajendran, Saranya; Abbasi Farid, Elnaz; 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 J.; Winterhoff, Boris J.N.; Topper, Michael J.; Sandusky, George E.; Miller, Kathy D.; Baylin, Stephen B.; Nephew, Kenneth P.; Rassool, Feyruz V.

doi:10.1158/0008-5472.28721646

Supplementary Data from ZNFX1 Functions as a Master Regulator of Epigenetically Induced Pathogen Mimicry and Inflammasome Signaling in Cancer

https://doi.org/10.1158/0008-5472.28721646

journal contribution

posted on 2025-04-03, 07:20 authored by Lora Stojanovic, Rachel Abbotts, Kaushelendra Tripathi, Collin M. Coon, Saranya Rajendran, Elnaz Abbasi Farid, Galen Hostetter, Joseph W. Guarnieri, Douglas C. Wallace, Sheng Liu, Jun Wan, Gennaro Calendo, Rebecca Marker, Zahra Gohari, Mohammed M.A. Inayatullah, Vijay K. Tiwari, Tanjina Kader, Sandro Santagata, Ronny Drapkin, Stefan Kommoss, Jacobus Pfisterer, Gottfried E. Konecny, Ryan Coopergard, Jean-Pierre J. Issa, Boris J.N. Winterhoff, Michael J. Topper, George E. Sandusky, Kathy D. Miller, Stephen B. Baylin, Kenneth P. Nephew, Feyruz V. Rassool

<p>Supplementary Figures</p>

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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National Institute of Environmental Health Sciences (NIEHS)

United States Department of Health and Human Services

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Van Andel Institute (VAI)

Gray Family Foundation (GFF)

Adelson Family Foundation (AFF)

History

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1.
DOI - Is supplement to ZNFX1 Functions as a Master Regulator of Epigenetically Induced Pathogen Mimicry and Inflammasome Signaling in Cancer

ARTICLE ABSTRACT

DNA methyltransferase (DNMT) and PARP inhibitors induce a stimulator of IFN gene–dependent pathogen mimicry response (PMR) in ovarian and other cancers. In this study, we showed that combining DNMT and PARP inhibitors upregulates expression of the nucleic acid sensor NFX1-type zinc finger–containing 1 (ZNFX1) protein. ZNFX1 mediated the induction of PMR in mitochondria, serving as a gateway for stimulator of IFN gene–dependent IFN/inflammasome signaling. Loss of ZNFX1 in ovarian cancer cells promoted proliferation and spheroid formation in vitro and tumor growth in vivo. In patient ovarian cancer databases, expression of ZNFX1 was elevated in advanced stage disease, and ZNFX1 expression alone significantly correlated with an increase in overall survival in a phase III trial for patients with therapy-resistant ovarian cancer receiving bevacizumab in combination with chemotherapy. RNA sequencing revealed an association between inflammasome signaling through ZNFX1 and abnormal vasculogenesis. Together, this study identified that ZNFX1 is a tumor suppressor that controls PMR signaling through mitochondria and may serve as a biomarker to facilitate personalized therapy in patients with ovarian cancer.Significance: DNMT and PARP inhibitors induce a nucleic acid sensor, ZNFX1, that serves as a mitochondrial gateway to STING-dependent inflammasome signaling with tumor suppressor properties in ovarian cancer.