KDM4C-Driven Epigenetic Mechanisms of Temozolomide Resistance: A Systematic Review
Keywords:
KDM4C, Temozolomide resistance, glioblastoma, epigenetics, histone demethylases, chemotherapy resistance, adaptive resistance, therapeutic targeting.Abstract
Background: Glioblastoma (GBM) is a highly aggressive brain tumor that is notoriously resistant to conventional chemotherapy, particularly Temozolomide (TMZ). Epigenetic modifications play a crucial role in the development of chemotherapy resistance, with histone demethylases such as KDM4C emerging as key regulators in this process. This systematic review aims to evaluate the current evidence on KDM4C-driven epigenetic mechanisms underlying TMZ resistance in GBM.
Objective: To investigate the role of KDM4C in mediating TMZ resistance in glioblastoma and to explore the potential of targeting KDM4C as a therapeutic strategy to overcome resistance.
Methods: A systematic search was conducted across multiple electronic databases, including PubMed, Embase, and Web of Science, to identify studies that examined the role of KDM4C in GBM and its contribution to TMZ resistance. Both in vitro and in vivo studies were included. Studies were assessed for quality and risk of bias, and key findings were extracted and synthesized.
Results: Five studies were included in this review. The evidence suggests that KDM4C plays a central role in conferring resistance to TMZ by modulating epigenetic changes, such as histone methylation, which regulate the expression of survival-related genes. Overexpression of KDM4C in GBM cells has been shown to upregulate cell survival pathways and cell-cycle regulators, contributing to TMZ resistance. Conversely, knockdown or inhibition of KDM4C restores sensitivity to TMZ, indicating its potential as a therapeutic target. Additionally, the KDM family, including KDM4C, appears to act in concert, with multiple KDMs contributing to the resistance phenotype. The role of adaptive resistance through epigenetic reprogramming was also highlighted, with KDM4C playing a key role in facilitating the survival of tumor cells under chemotherapy-induced stress.
Conclusions: KDM4C is a critical mediator of TMZ resistance in glioblastoma, functioning through epigenetic reprogramming that supports tumor cell survival and proliferation. Targeting KDM4C, either alone or in combination with other KDM inhibitors, holds potential as a novel therapeutic strategy to overcome TMZ resistance. However, further in vivo and clinical studies are needed to validate these findings and assess the feasibility of targeting KDM4C in GBM therapy..
