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ATRX loss inhibits DDR to strengthen radio-sensitization in p53-deficent HCT116 cells

Lijing Qin1, Geng Tang1, Ruirui Gui1

  • 1NHC Key Laboratory of Radiobiology (Jilin University), School of Public Health, Jilin University, Changchun, 130021, Jilin, People's Republic of China.

Scientific Reports
|January 4, 2025
PubMed

Insights

Alpha-thalassemia/mental retardation X-linked (ATRX) silencing enhances colorectal cancer (CRC) cell radiosensitivity, particularly when p53 is depleted. ATRX loss promotes apoptosis and DNA damage response, suggesting ATRX as a radiosensitizing target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Radiotherapy

Background:

  • Radiotherapy is a cornerstone of colorectal cancer (CRC) treatment, but resistance limits efficacy.
  • Identifying novel molecular targets for radiosensitization is crucial for improving patient outcomes.
  • Alpha-thalassemia/mental retardation X-linked (ATRX) is a chromatin remodeler involved in genomic stability, but its role in CRC radiosensitivity is unknown.

Purpose of the Study:

  • To investigate the role of ATRX in the radiosensitivity of colorectal cancer (CRC) cells.
  • To elucidate the underlying molecular mechanisms by which ATRX influences response to ionizing radiation (IR).

Main Methods:

  • Silencing of ATRX in HCT116 CRC cells using shRNA.
  • Irradiation of cells and assessment of DNA damage response (DDR), apoptosis, and senescence.
  • Analysis of the Daxx/MDM2/p53 pathway activation and ATM/Chk2 signaling.

Main Results:

  • ATRX depletion significantly increased radiosensitivity in HCT116 CRC cells, an effect amplified by p53 depletion.
  • ATRX loss led to IR-induced DNA damage and G2/M arrest, with impaired ATM/Chk2 pathway activation.
  • ATRX deficiency promoted apoptosis and attenuated senescence, mediated by upregulation of p53 function via the Daxx/MDM2 pathway.

Conclusions:

  • ATRX plays a critical role in regulating colorectal cancer cell radiosensitivity.
  • ATRX loss impairs the DNA damage response and promotes apoptosis, enhancing radiosensitivity.
  • ATRX represents a potential novel radiosensitizing target for CRC, especially in p53-deficient tumors.
Keywords:
ATRXColorectal cancerDNA damage responseDaxx/MDM2/p53 pathwayRadiosensitivity

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