m6A demethylase FTO renders radioresistance of nasopharyngeal carcinoma via promoting OTUB1-mediated anti-ferroptosis

by Selleckchem | Aug 31 2023

Radiotherapy is a valid treatment for nasopharyngeal carcinoma (NPC), and radioresistance is the main cause of local NPC treatment failure. However, the underlying mechanisms and valuable markers of radioresistance for NPC remain have not been established. In this study, we observed that the m6A mRNA demethylase fat mass and obesity-associated protein (FTO) was significantly upregulated in radioresistant NPC tissues and cells relative to parental radiosensitive NPC tissues and cells. FTO enhances radioresistance by repressing radiation-induced ferroptosis in NPC. Mechanistically, FTO acts as an m6A demethylase to erase the m6A modification of the OTUB1 transcript and promote the expression of OTUB1, thereby inhibiting the ferroptosis of cells induced by radiation and finally triggering the radiotherapy resistance of NPC. Furthermore, our in vivo experiment results showed that the FTO inhibitor, FB23-2, and the ferroptosis activator, erastin, altered tumor responsiveness to radiotherapy in NPC cell lines and patient-derived xenografts. Our findings reveal, for the first time, that FTO enhances NPC radiotherapy resistance by withstanding radiation-induced ferroptosis, suggesting that FTO may serve as a potential therapeutic target and valuable prognostic biomarker in patients with NPC.

Comments:

The study you described provides important insights into the mechanisms of radioresistance in nasopharyngeal carcinoma (NPC) and highlights the potential role of the m6A mRNA demethylase fat mass and obesity-associated protein (FTO) in this process. The researchers found that FTO was significantly upregulated in radioresistant NPC tissues and cells compared to radiosensitive ones. They demonstrated that FTO promotes radioresistance by suppressing radiation-induced ferroptosis, a form of programmed cell death characterized by the accumulation of reactive oxygen species (ROS) and lipid peroxidation.

The mechanism underlying FTO-mediated radioresistance involves its function as an m6A demethylase, which removes the m6A modification on the OTUB1 transcript. This results in increased expression of OTUB1, which inhibits ferroptosis induced by radiation. By blocking ferroptosis, FTO enables NPC cells to evade the lethal effects of radiotherapy, leading to treatment resistance.

In addition to in vitro studies, the researchers also conducted in vivo experiments using NPC cell lines and patient-derived xenografts. They found that treatment with an FTO inhibitor called FB23-2 and a ferroptosis activator called erastin could alter tumor responsiveness to radiotherapy, suggesting that targeting FTO or promoting ferroptosis could be potential strategies to overcome radioresistance in NPC.

These findings highlight FTO as a potential therapeutic target and valuable prognostic biomarker in patients with NPC. Targeting FTO or ferroptosis pathways may help to overcome radioresistance and improve the effectiveness of radiotherapy in treating NPC. However, it's important to note that further studies and clinical trials are needed to validate these findings and explore the translational potential of targeting FTO in NPC treatment.