Targeting BRF2 in Cancer Using Repurposed Drugs.

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• BRF2, a subunit of RNA polymerase III, is overexpressed in cancers like breast and lung cancer.
• BRF2 functions as a redox-sensing transcription factor, protecting cells from oxidative stress-induced apoptosis.
• The role of BRF2 in DNA damage response (DDR) is not well understood.

Purpose of the Study:

• To investigate the novel link between BRF2 and the DNA damage response.
• To identify potential BRF2 inhibitors due to the lack of specific drugs.
• To evaluate bexarotene as a potential BRF2 inhibitor for cancer therapy.

Main Methods:

• Virtual screening and molecular dynamics simulations to identify drug candidates targeting the BRF2-TBP-DNA complex.
• Experimental validation of bexarotene as a BRF2 inhibitor.
• Assessment of bexarotene's effects on oxidative stress, BRF2 levels, and cancer cell proliferation.

Main Results:

• Bexarotene treatment significantly reduced oxidative stress and Tert-butylhydroquinone (tBHQ)-induced BRF2 levels.
• Bexarotene decreased cancer cell proliferation, potentially by reducing reactive oxygen species (ROS).
• Identification of bexarotene as a potential inhibitor interfering with BRF2-TBP-DNA interactions.

Conclusions:

• BRF2 is a novel player in the DNA damage response pathway.
• Bexarotene demonstrates potential as a therapeutic agent for cancers characterized by elevated oxidative stress.
• Targeting BRF2 offers a new strategy for cancer treatment, particularly in managing oxidative stress.