Regulatory mechanisms of O6-methylguanine methyltransferase expression in glioma cells

O6-methylguanine methyltransferase (MGMT), a pivotal DNA repair enzyme, has its dysregulation playing a substantial role in gliomagenesis, the development of therapeutic resistance, and patient prognosis. This narrative review is designed to offer an all-encompassing overview of the intricate regulatory mechanisms that govern MGMT expression in glioma cells. We systematically investigate the diverse levels of regulation that impact MGMT expression in glioma. These include epigenetic regulation, transcriptional control, post-translational modifications, and the influence exerted by the tumor microenvironment. Epigenetically, methylation of CpG islands within the MGMT promoter region represents a critical determinant for gene silencing. Conversely, histone modifications such as H3K4me3 augment MGMT expression. Transcriptionally, a complex network of transcription factors, which encompasses Sp1, p53, and NF-κB, along with signaling pathways like TGF-β, JAK/STAT, and PI3K/AKT, orchestrates MGMT expression in glioma cells. Furthermore, post-translational modifications of MGMT, such as phosphorylation and ubiquitination, are of pivotal importance in modulating its stability and enzymatic activity. The tumor microenvironment, with factors such as oxidative stress, hypoxia, and immune responses, also exerts a significant influence on MGMT expression. This narrative review delves deeper into the relationship between MGMT expression and drug resistance, especially resistance to alkylating chemotherapy agents, and accentuates the significance of evaluating MGMT expression for personalized glioma therapy. By elucidating these regulatory mechanisms, this review endeavors to enhance our understanding of MGMT's role in glioma biology and to provide insights for future therapeutic strategies aimed at surmounting current treatment challenges.