UVC inhibits HIF-1alpha protein translation by a DNA damage- and topoisomerase I-independent pathway

Area of Science:

• Oncology
• Molecular Biology
• Cellular Biology

Background:

• Hypoxia-inducible factor 1 (HIF-1) is crucial in cancer progression and a therapeutic target.
• Small molecule HIF-1alpha inhibitors often trigger DNA damage responses, but the link is unclear.

Purpose of the Study:

• To investigate how different DNA damaging conditions affect hypoxic induction of HIF-1alpha protein in cancer cells.
• To elucidate the relationship between DNA damage and HIF-1alpha inhibition.

Main Methods:

• Cancer cell lines were exposed to various DNA damaging agents (UVC, cisplatin, ionizing radiation, doxorubicin, topotecan).
• HIF-1alpha protein accumulation was measured under hypoxic conditions.
• Effects on translation, global protein synthesis, RNA transcription, and DNA replication were assessed.
• The role of ATR and topoisomerase I in UVC-induced inhibition was examined.

Main Results:

• UVC, but not other agents, inhibited HIF-1alpha protein accumulation dose-dependently and independent of p53.
• Low-dose UVC reduced HIF-1alpha translation without impacting global protein synthesis.
• UVC-induced HIF-1alpha inhibition required RNA transcription but not DNA replication.
• ATR was necessary for UVC/TPT DNA damage responses but not for HIF-1alpha inhibition by UVC.
• UVC inhibited HIF-1alpha without requiring topoisomerase I, unlike TPT.

Conclusions:

• UVC is a novel signal that inhibits HIF-1alpha protein accumulation.
• The DNA damage signaling pathway activated by UVC and TPT is distinct from HIF-1alpha inhibition.
• This study uncouples DNA damage signaling from HIF-1alpha inhibition, offering new therapeutic insights.