G-protein coupled estrogen receptor 1 (GPER1) expression improves survival of glioblastoma patients depending on sex and age: biological mechanisms and epigenetic regulation

Introduction In 2021, WHO classification of brain tumors adopted an integrated approach, combining histopathological features with key molecular alterations, notably redefining astrocytoma and glioblastoma entities. Among gliomas, glioblastoma has the worst prognosis, with a median patient survival rate of no more than 15 months. To date, no treatment is effective and there is no targeted therapy available. Recent research underscores the influence of sex and sex hormones in gliomagenesis, development and response to treatment. Indeed, glioblastoma exhibit sex-based disparities in adults, with a higher incidence of these tumors and shorter survival in males compared to females. Sex differences tend to narrow in older populations, suggesting that beside genetic sex or acquired gender-biased specificities, sex hormones play a significant role in this difference. Among the key hormone receptors potentially involved, we focused on GPER, the membrane g-coupled estrogen receptor. Methods Expression, methylation and clinical data from TCGA-LGG and TCGA-GBM datasets were reclassified according to WHO 2021. GPER1 expression level was correlated to patient overall survival and methylation status of the GPER1 locus. Underlying mechanisms were unraveled in vitro by transcriptomic and functional analyses of GPER-overexpressing cells. Results A high expression of GPER1 predicted overall survival depending on age and sex, especially for females aged less than 55 years. Functional analysis of GPER1 -correlated genes indicated that GPER1 high expression is associated with cell cycle impairment. In vitro, GPER protein overexpression impaired U251 cell proliferation, which confirmed the benefice of GPER1 high expression against glioblastoma. Since methylation of GPER1 locus was previously shown to control its expression in other cancers, we finally identified 3 CpG sites whose methylation level were inversely correlated with GPER1 expression. Interestingly, the combined low methylation level of these 3 CpG sites is associated with prolonged overall survival in females under the age of 55, suggesting that methylation at these loci may contribute to GPER1 expression control in glioblastoma. Conclusion The present findings identify a potential mechanism of GPER1 regulation in glioblastoma and suggest that GPER could be a therapeutic target of interest, notably for non-menopaused women.