Long non-coding RNA ATXN8OS promotes ferroptosis and inhibits the temozolomide-resistance of gliomas through the...

Area of Science:

• Neuro-oncology
• Epigenetics
• Cancer Biology

Background:

• Gliomas are the most common malignant brain tumors with poor prognosis.
• Chemotherapy resistance, particularly to temozolomide (TMZ), is a major challenge in glioma treatment.
• Ferroptosis, a form of regulated cell death, is linked to drug resistance in various cancers.

Purpose of the Study:

• To investigate the epigenetic mechanisms underlying chemotherapy resistance in glioma.
• To explore the role of long non-coding RNA ATXN8 opposite strand (ATXN8OS) in modulating temozolomide resistance.
• To elucidate the molecular pathway involving ATXN8OS in glioma chemoresistance.

Main Methods:

• Quantitative real-time PCR and Western blot to assess gene and protein expression.
• Cellular assays including ferrous iron and reactive oxygen species detection.
• Functional experiments with glioma cell lines and xenograft models.
• Subcellular fractionation, FISH, RNA immunoprecipitation (RIP), and RNA pull-down assays to identify RNA-protein interactions.

Main Results:

• ATXN8OS expression was significantly lower in glioma cell lines.
• Overexpression of ATXN8OS inhibited TMZ resistance in glioma cells and xenografts.
• ATXN8OS was identified as a cytoplasmic molecule interacting with ADAR (adenosine deaminase acting on RNA).
• ATXN8OS recruits ADAR to stabilize glutaminase 2 (GLS2) mRNA, thereby restraining TMZ resistance.
• Rescue experiments confirmed that ATXN8OS modulates TMZ resistance through the ADAR/GLS2 pathway.

Conclusions:

• ATXN8OS plays a crucial role in overcoming temozolomide resistance in glioma.
• The ATXN8OS/ADAR/GLS2 axis mediates ferroptosis and regulates chemoresistance in glioma.
• Targeting the ATXN8OS/ADAR/GLS2 pathway presents a potential therapeutic strategy for improving glioma treatment outcomes.