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

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

doi:10.1158/0008-5472.CAN-24-1286

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

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 KommossJacobus 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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.

Original language	English
Journal	Cancer Research
Volume	85
Issue number	7
Pages (from-to)	1183-1198
ISSN	0008-5472
DOIs	https://doi.org/10.1158/0008-5472.CAN-24-1286
Publication status	Published - 1. Apr 2025

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Stojanovic, L., Abbotts, R., Tripathi, K., Coon, C. M., Rajendran, S., Farid, E. A., 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., ... Rassool, F. V. (2025). ZNFX1 Functions as a Master Regulator of Epigenetically Induced Pathogen Mimicry and Inflammasome Signaling in Cancer. Cancer Research, 85(7), 1183-1198. https://doi.org/10.1158/0008-5472.CAN-24-1286

@article{1ca1ede29758489dba6a08cd30928921,

title = "ZNFX1 Functions as a Master Regulator of Epigenetically Induced Pathogen Mimicry and Inflammasome Signaling in Cancer",

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.",

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

year = "2025",

month = apr,

day = "1",

doi = "10.1158/0008-5472.CAN-24-1286",

language = "English",

volume = "85",

pages = "1183--1198",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "7",

}

Stojanovic, L, Abbotts, R, Tripathi, K, Coon, CM, Rajendran, S, Farid, EA, Hostetter, G, Guarnieri, JW, Wallace, DC, Liu, S, Wan, J, Calendo, G, Marker, R, Gohari, Z, Inayatullah, MMA , Tiwari, VK, Kader, T, Santagata, S, Drapkin, R, Kommoss, S, Pfisterer, J, Konecny, GE, Coopergard, R, Issa, JPJ, Winterhoff, BJN, Topper, MJ, Sandusky, GE, Miller, KD, Baylin, SB, Nephew, KP & Rassool, FV 2025, 'ZNFX1 Functions as a Master Regulator of Epigenetically Induced Pathogen Mimicry and Inflammasome Signaling in Cancer', Cancer Research, vol. 85, no. 7, pp. 1183-1198. https://doi.org/10.1158/0008-5472.CAN-24-1286

TY - JOUR

T1 - ZNFX1 Functions as a Master Regulator of Epigenetically Induced Pathogen Mimicry and Inflammasome Signaling in Cancer

AU - Stojanovic, Lora

AU - Abbotts, Rachel

AU - Tripathi, Kaushelendra

AU - Coon, Collin M.

AU - Rajendran, Saranya

AU - Farid, Elnaz Abbasi

AU - Hostetter, Galen

AU - Guarnieri, Joseph W.

AU - Wallace, Douglas C.

AU - Liu, Sheng

AU - Wan, Jun

AU - Calendo, Gennaro

AU - Marker, Rebecca

AU - Gohari, Zahra

AU - Inayatullah, Mohammed M.A.

AU - Tiwari, Vijay K.

AU - Kader, Tanjina

AU - Santagata, Sandro

AU - Drapkin, Ronny

AU - Kommoss, Stefan

AU - Pfisterer, Jacobus

AU - Konecny, Gottfried E.

AU - Coopergard, Ryan

AU - Issa, Jean Pierre J.

AU - Winterhoff, Boris J.N.

AU - Topper, Michael J.

AU - Sandusky, George E.

AU - Miller, Kathy D.

AU - Baylin, Stephen B.

AU - Nephew, Kenneth P.

AU - Rassool, Feyruz V.

PY - 2025/4/1

Y1 - 2025/4/1

N2 - 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.

AB - 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.

U2 - 10.1158/0008-5472.CAN-24-1286

DO - 10.1158/0008-5472.CAN-24-1286

M3 - Journal article

C2 - 39804147

AN - SCOPUS:105001810650

SN - 0008-5472

VL - 85

SP - 1183

EP - 1198

JO - Cancer Research

JF - Cancer Research

IS - 7

ER -

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

Abstract

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