Long non-coding RNA ATXN8OS promotes ferroptosis and inhibits the temozolomide-resistance of gliomas through the ADAR/GLS2 pathway

Abstract

As the most common malignant tumor, gliomas remain a poor prognosis while chemotherapy resistance is a medical problem for the treatment of glioma. Considering the correlation between drug resistance and ferroptosis, this study aims to explore the mechanism of chemotherapy resistance in glioma from the perspective of epigenetics. Because of the low expression of long non-coding RNA (lncRNA) ATXN8 opposite strand (ATXN8OS) in glioma cell lines, the role of ATXN8OS was explored by the detection on ferrous iron (Fe2+)/lipid reactive oxygen species (ROS), function experiments and assays performed with xenograft model, proving that ATXN8OS inhibited temozolomide (TMZ)-resistance of glioma. After subcellular fractionation and FISH assays revealed that ATXN8OS was mainly located in cytoplasm, we determined the RNA binding protein (RBP) of ATXN8OS as adenosine deaminase acting on RNA (ADAR) via RNA binding protein immunoprecipitation (RIP), RNA pull down and western blot assays. Furthermore, we verified that ATXN8OS stabilized glutaminase 2 (GLS2) mRNA by recruiting ADAR and GLS2 restrained TMZ-resistance of glioma both in vitro and in vivo. Rescue experiments indicated that ATXN8OS modulated TMZ-resistance of glioma through GLS2. In conclusion, ATXN8OS mediated ferroptosis and regulated the TMZ-resistance of glioma via ADAR/GLS2 pathway.

Keywords

• ATXN8OS
• Gliomas
• ADAR
• Ferroptosis
• TMZ-resistance