Role of non-coding RNAs in O⁶-methylguanine-DNA methyltransferase-positive glioblastoma (Review)

Glioblastoma (GBM) is the most aggressive primary tumor of the central nervous system. The standard treatment consists of maximal surgical resection followed by concurrent radiotherapy and temozolomide (TMZ) chemoradiotherapy; however, the frequent emergence of TMZ resistance remains a major determinant of poor prognosis. The expression of O⁶-methylguanine-DNA methyltransferase (MGMT) represents a central mechanism underlying resistance to TMZ chemotherapy. Although MGMT expression is primarily regulated by the methylation status of its promoter, it is also influenced by additional regulatory mechanisms. The present review therefore aims to systematically summarize the current understanding of how non-coding RNAs (ncRNAs), as key regulators, govern MGMT expression and contribute to this complex regulatory network. Specifically, it focuses on the roles of microRNAs (miRNAs/miRs), long ncRNAs (lncRNAs) and circular RNAs (circRNAs) in regulating MGMT expression. miRNAs regulate MGMT by directly binding to its mRNA or indirectly modulating upstream transcription factors. lncRNAs primarily act indirectly through competing endogenous RNA (ceRNA) networks, epigenetic remodeling or modulation of signaling pathways. circRNAs, often functioning as stable ceRNA molecules, provide an additional layer of complexity and stability in this regulatory network. Notably, interactions among different ncRNAs may be synergistic or antagonistic. Examples include the cooperative repression of MGMT by miR-181d and miR-409-3p, and the sequestration of miR-182-5p by lncRNA urothelial carcinoma-associated 1. Overall, the findings suggested that MGMT expression is governed by a dynamic, multi-layered regulatory system. Understanding this network has notable implications for elucidating GBM chemoresistance and identifying novel therapeutic strategies to reverse drug resistance.