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

Lora Stojanovic1,2, Rachel Abbotts1,2, Kaushlendra Tripathi1,2

  • 1University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA.

Biorxiv : the Preprint Server for Biology
|November 1, 2024
PubMed

Insights

DNA methyltransferase and poly(ADP-ribose) polymerase inhibitors (DNMTis, PARPis) activate a pathogen mimicry response (PMR). ZNFX1 protein is a novel master regulator of this response, potentially serving as a biomarker for ovarian cancer therapy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • DNA methyltransferase inhibitors (DNMTis) and poly(ADP-ribose) polymerase inhibitors (PARPis) induce a stimulator of interferon genes (STING)-dependent pathogen mimicry response (PMR) in ovarian cancer (OC).
  • The precise molecular mechanisms and regulators of this PMR are not fully understood.

Purpose of the Study:

  • To investigate the role of the nucleic-acid sensor ZNFX1 in DNMTi and PARPi-induced PMR.
  • To determine ZNFX1's potential as a biomarker and therapeutic target in ovarian cancer.

Main Methods:

  • Analysis of ovarian cancer patient databases and correlative RNA-sequencing data.
  • Investigating ZNFX1's function in regulating mitochondrial pathogen mimicry response (PMR) and STING signaling.

Main Results:

  • Combining DNMTis and PARPis upregulates ZNFX1 expression.
  • ZNFX1 acts as a master regulator of mitochondrial PMR induction, serving as a gateway for STING-dependent PMR.
  • High ZNFX1 expression correlates with advanced OC stage but also with increased overall survival in therapy-resistant patients treated with bevacizumab and chemotherapy.

Conclusions:

  • ZNFX1 is a novel key regulator of the STING-dependent pathogen mimicry response in ovarian cancer.
  • ZNFX1 may serve as a predictive biomarker for personalized therapy, particularly in combination with bevacizumab and chemotherapy for therapy-resistant ovarian cancer.
Keywords:
DNA damageSTINGZNFX1inflammasomeinterferonmitochondriaovarian cancerreactive oxygen speciestumor suppressorviral mimicry

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