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The oncogene ATF3 is potentiated by cyclosporine A and ultraviolet light A

Piotr J Dziunycz1, Karine Lefort2, Xunwei Wu3

  • 1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

The Journal of Investigative Dermatology
|February 11, 2014
PubMed

Insights

Activating transcription factor 3 (ATF3) drives skin cancer in organ transplant patients. UV radiation and calcineurin inhibitors synergistically increase ATF3, promoting cutaneous squamous cell carcinoma (SCC) development on sun-exposed skin.

Area of Science:

  • Dermatology
  • Oncology
  • Immunology

Background:

  • Cutaneous squamous cell carcinoma (SCC) is a significant complication in organ transplant recipients, often appearing on sun-exposed skin.
  • Activating transcription factor 3 (ATF3) has been implicated in SCC development, potentially acting as an oncogene.
  • Existing research suggests calcineurin inhibitors upregulate ATF3, but this doesn't fully explain SCC's predilection for sun-damaged skin.

Purpose of the Study:

  • To investigate the influence of UV radiation on ATF3 expression in the context of organ transplantation and SCC development.
  • To elucidate the molecular mechanisms underlying ATF3 induction by UV radiation and calcineurin inhibitors.

Main Methods:

  • Analysis of ATF3 expression in SCC from transplanted patients.
  • Investigating the synergistic effects of cyclosporine A (a calcineurin inhibitor) and UVA irradiation on ATF3 levels.
  • Examining the role of reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (NRF2) in UVA-induced ATF3 expression.

Main Results:

  • ATF3 was identified as a key AP1 member specifically induced in SCC of transplant patients.
  • Cyclosporine A and UVA treatment synergistically potentiated ATF3 expression.
  • UVA induced ATF3 expression via ROS-mediated NRF2 activation, independent of calcineurin/NFAT signaling.
  • Activated NRF2 directly binds to the ATF3 promoter, driving its expression.

Conclusions:

  • Two distinct mechanisms independently induce, and synergistically potentiate, ATF3 expression.
  • These mechanisms provide a molecular explanation for the high incidence of SCC on sun-exposed skin in organ transplant recipients treated with calcineurin inhibitors.
  • Targeting ATF3 may offer a therapeutic strategy for preventing or treating transplant-associated SCC.

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