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Inhibition of demethylase by IOX1 modulates chromatin accessibility to enhance NSCLC radiation sensitivity through

Qian Li1, Kexin Qin2, Yushan Tian3

  • 1School of Environmental Science and Optoelectronic Technology, University of Science and Technology of China, Hefei, Anhui, 230026, PR China.

Cell Death & Disease
|December 12, 2023
PubMed

Insights

The histone demethylase inhibitor IOX1 enhances radiosensitivity in non-small cell lung cancer (NSCLC) by reducing DNA repair and increasing telomere damage. This occurs through decreased chromatin accessibility and inhibition of phytochrome interacting factor 1 (PIF1).

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Chromatin accessibility, regulated by histone modifications, influences gene expression.
  • The role of manipulating chromatin accessibility in radiation sensitivity is not well understood.
  • Non-small cell lung cancer (NSCLC) presents a significant challenge in radiation therapy.

Purpose of the Study:

  • To investigate the effect of the histone demethylase inhibitor IOX1 on NSCLC radiosensitivity.
  • To elucidate the molecular mechanisms by which IOX1 impacts radiation response.
  • To explore the role of phytochrome interacting factor 1 (PIF1) in IOX1-mediated radiosensitization.

Main Methods:

  • In vitro and in vivo experiments using NSCLC models.
  • Assessment of chromatin accessibility using techniques like ATAC-seq (not explicitly stated but implied).
  • Analysis of DNA damage repair efficiency, gene transcription, and telomere maintenance.

Main Results:

  • IOX1 treatment significantly enhanced radiosensitivity in NSCLC.
  • IOX1 reduced chromatin accessibility in DNA damage repair gene promoters, impairing repair and increasing γ-irradiation-induced damage.
  • IOX1 inhibited PIF1 transcription and function, delaying DNA and telomeric damage repair, which was linked to reduced MAZ binding to the PIF1 gene.

Conclusions:

  • IOX1 enhances NSCLC radiosensitivity by reducing chromatin accessibility and impairing DNA damage repair.
  • Inhibition of PIF1 contributes to increased radiosensitivity by affecting telomere maintenance and repair.
  • IOX1 represents a potential therapeutic strategy to improve radiation outcomes in NSCLC.

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