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

Lora Stojanovic1,2, Rachel Abbotts1,2, Kaushelendra Tripathi1,2

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

Cancer Research
|January 13, 2025
PubMed

Insights

DNA methyltransferase (DNMT) and PARP inhibitors upregulate ZNFX1, a protein that triggers a pathogen mimicry response (PMR). ZNFX1 acts as a tumor suppressor in ovarian cancer, potentially serving as a biomarker for personalized therapy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • DNA methyltransferase (DNMT) and PARP inhibitors can induce a pathogen mimicry response (PMR) in various cancers.
  • This response is dependent on the stimulator of IFN genes (STING).

Purpose of the Study:

  • To investigate the role of ZNFX1 in mediating the PMR induced by DNMT and PARP inhibitors.
  • To explore ZNFX1's function as a tumor suppressor in ovarian cancer and its potential as a therapeutic biomarker.

Main Methods:

  • Combining DNMT and PARP inhibitors in cancer cells.
  • Assessing ZNFX1 protein expression and its role in signaling pathways.
  • In vitro and in vivo functional assays to evaluate ZNFX1's impact on cancer cell proliferation and tumor growth.
  • Analysis of patient ovarian cancer databases and clinical trial data.

Main Results:

  • Combined DNMT and PARP inhibition upregulated ZNFX1 expression.
  • ZNFX1 mediated PMR through mitochondria, acting as a gateway for STING-dependent IFN/inflammasome signaling.
  • Loss of ZNFX1 promoted ovarian cancer cell proliferation, spheroid formation, and tumor growth.
  • Elevated ZNFX1 expression correlated with advanced disease but also with increased survival in therapy-resistant ovarian cancer patients.
  • ZNFX1 signaling was associated with abnormal vasculogenesis.

Conclusions:

  • ZNFX1 is a tumor suppressor that regulates mitochondrial PMR signaling.
  • ZNFX1 acts as a crucial mediator in the STING-dependent inflammasome pathway.
  • ZNFX1 may serve as a valuable biomarker for personalized therapeutic strategies in ovarian cancer.

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