Targeting BRF2 in Cancer Using Repurposed Drugs

Simple Summary BRF2, a subunit of the RNA polymerase III transcription complex, is upregulated in a wide variety of cancers and is a potential therapeutic target; however, no effective drugs are available to target BRF2. The upregulation of BRF2 in cancer cells confers survival via the prevention of oxidative stress-induced apoptosis. In this manuscript, we report the identification of potential BRF2 inhibitors through in silico drug repurposing screening. We further characterized bexarotene as a hit compound for the development of selective BRF2 inhibitors and provide experimental validation to support the repurposing of this FDA-approved drug as an agent to reduce the cellular levels of ROS and consequent BRF2 expression in cancers with elevated levels of oxidative stress. The overexpression of BRF2, a selective subunit of RNA polymerase III, has been shown to be crucial in the development of several types of cancers, including breast cancer and lung squamous cell carcinoma. Predominantly, BRF2 acts as a central redox-sensing transcription factor (TF) and is involved in rescuing oxidative stress (OS)-induced apoptosis. Here, we showed a novel link between BRF2 and the DNA damage response. Due to the lack of BRF2-specific inhibitors, through virtual screening and molecular dynamics simulation, we identified potential drug candidates that interfere with BRF2-TATA-binding Protein (TBP)-DNA complex interactions based on binding energy, intermolecular, and torsional energy parameters. We experimentally tested bexarotene as a potential BRF2 inhibitor. We found that bexarotene (Bex) treatment resulted in a dramatic decline in oxidative stress and Tert-butylhydroquinone (tBHQ)-induced levels of BRF2 and consequently led to a decrease in the cellular proliferation of cancer cells which may in part be due to the drug pretreatment-induced reduction of ROS generated by the oxidizing agent. Our data thus provide the first experimental evidence that BRF2 is a novel player in the DNA damage response pathway and that bexarotene can be used as a potential inhibitor to treat cancers with the specific elevation of oxidative stress.