Downregulation of CYP2E1 is associated with poor prognosis and tumor progression of gliomas

Abstract

Objective To explore the role and possible regulatory mechanisms of CYP2E1 in gliomas. Methods RNA‑seq data and corresponding clinical information of glioma patients were collected from The Cancer Genome Atlas and Chinese Glioma Genome Atlas, and mRNA data of normal brain tissues were obtained by the Genotype‐Tissue Expression project. The Wilcoxon test was performed to analyze the correlation between CYP2E1 expression and glioma subtypes. Univariate and multivariate Cox proportional hazards regression, receiver operating characteristic curves, and Kaplan–Meier plots were used to evaluate the prognostic value of CYP2E1 in glioma. Functional enrichment analyses and immune infiltration analyses were performed to investigate the potential function of CYP2E1 in gliomas. Moreover, we investigated the miRNA and epigenetic mechanisms that regulate CYP2E1 expression. Finally, network pharmacology and molecular docking experiments were used to predict drugs that target CYP2E1. Results The downregulation of CYP2E1 expression may predict a poor prognosis for glioma patients. CYP2E1 expression decreased with increasing WHO grade (II–IV), and its level was correlated with clinical features, including age, 1p19q codeletion status, and IDH state in glioma tissues. Furthermore, CYP2E1 was involved in lipid metabolism and ferroptosis and related to the tumor immune microenvironment due to its strong correlation with the levels of infiltrating monocytes and Tregs. Moreover, variation in the total methylation level and copy number of CYP2E1 was moderately correlated with its mRNA expression (p < 0.05). CYP2E1 was predicted to be targeted by hsa‐miR‐527, whose expression was negatively related to CYP2E1 mRNA expression (p < 0.05). In addition, effective compounds that target CYP2E1, including 18beta‐glycyrrhetinic acid, styrene, toluene, nicotine, m‐xylene, p‐xylene, and colchicine, were identified. Conclusion The downregulation of CYP2E1, which affects lipid metabolism and the ferroptosis signaling pathway, promotes the progression of gliomas.

A lipid metabolism-related risk signature for patients with gliomas constructed with TCGA and CGGA data

“…[33][34][35][36] A previous study confirmed that CYP2E1 acts as a tumor suppressor in gliomas, consistent with our findings, suggesting that this hub gene could be a key target for follow-up studies. [37] The correlation analysis revealed that the risk score may be significantly correlated with various immunology-related parameters. Elevated expression of immune checkpoint proteins that facilitate immune escape was observed in high-risk patients with gliomas, and thus the microenvironment of high-risk patients .…”

Effects of ABCB1 DNA methylation in donors on tacrolimus blood concentrations in recipients following liver transplantation

“…Recently, epigenetic modifications, which regulate the expression of several enzymes and transporters involved in drug metabolism, have been recognised as important factors that affect individual differences in clinical drug response 21 . DNA methylation affects the expression of CYP450 ( CYP1A1 , CYP1A2 , CYP1B1 , CYP2C19 , CYP2D6 , CYP2E1 and CYP2W1 ), thus leading to significant individual differences in enzyme expression 22–25 . In addition, DNA methylation regulates the expression of ABCG2 and ABCB1 , which play a crucial role in determining the success or failure of cancer chemotherapy by mediating multidrug resistance and individual differences in drug transport 26,27 .…”

“…21 DNA methylation affects the expression of CYP450 (CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, CYP2E1 and CYP2W1), thus leading to significant individual differences in enzyme expression. [22][23][24][25] In addition, DNA methylation regulates the expression of ABCG2 and ABCB1, which play a crucial role in determining the success or failure of cancer chemotherapy by mediating multidrug resistance and individual differences in drug transport. 26,27 As most studies on the methylation of genes encoding drug transporters have been carried out in the field of oncology, we investigated, for the first time, whether ABCB1 DNA methylation in donor livers affects tacrolimus blood concentrations in liver transplant recipients by regulating its expression.…”

Ferroptosis Modulation: Potential Therapeutic Target for Glioblastoma Treatment

“…For instance, CYP2E1 activity produces acetaldehyde and ROS, increasing lipid peroxidation and promoting ferroptosis. Glioma patients with low levels of CYP2E1 have a poor prognosis since the downregulation of this gene affects lipid metabolism and prevents ferroptosis in tumor tissues, leading to glioma progression [46]. Additionally, MDM2 and MDMX promote ferroptosis in a p53-independent manner by modulating lipid activity through PPARα regulation and by inhibiting the activity of lipophilic antioxidants via FSP1 protein regulation [47].…”