Downregulated ferroptosis-related gene SQLE facilitates temozolomide chemoresistance, and invasion and affects immune regulation in glioblastoma

Abstract

Chemoresistance in patients with glioblastoma multiforme (GBM) is a common reason hindering the success of treatment. Recently, ferroptosis has been reported to be associated with chemoresistance in different types of cancer, while the role of ferroptosis-related genes in GBM have not been fully elucidated. This study aimed to demonstrate the roles and mechanism of ferroptosis-related genes in chemoresistance and metastasis of GBM. First, two candidate genes, squalene epoxidase (SQLE) and FANCD2, were identified to be associated with ferroptosis-related chemoresistance in GBM from three temozolomide (TMZ) therapeutic datasets and one ferroptosis-related gene dataset. Then, comprehensive bio-informatics data from different databases testified that SQLE was significantly downregulated both in GBM tissue and cells and displayed a better prognosis in GBM. Clinical data identified lower expression of SQLE was significantly associated with WHO grade and 1p/19q codeletion. Moreover, through in vitro experiments, SQLE was confirmed to suppress ERK-mediated TMZ chemoresistance and metastasis of GBM cells. The KEGG analysis of SQLE-associated co-expressed genes indicated SQLE was potentially involved in the cell cycle. Furthermore, SQLE was found to have the most significant correlations with tumor-infiltrating lymphocytes and immunomodulators. These findings highlighted that SQLE could be a potential target and a biomarker for therapy and prognosis of patients with GBM.