DNMT1 drives glioma progression and modulates therapy response: A novel therapeutic target

Gliomas are heterogenous, invasive glial tumors characterized by the interplay of genetic and epigenetic changes. Emerging evidence indicates that aberrant activity of the DNA (cytosine-5) methyltransferase 1, DNMT1 may play a significant role in glioma development, and progression, maintaining cancer stem cells stemness via hypermethylation of promoter gene regions with a negative impact in DNA repair, cell apoptosis and differentiation genes. At the same time, lower expression or absence of DNMT1 has been associated with global gene hypomethylation, contributing to genome instability and cancer onset. Interaction of DNMT1 with histone deacetylases (HDACs) and polycomb repressive complexes (PRCs) establishes a repressive chromatin state, further contributing to silencing of tumor suppressor genes and enabling glioma growth and invasion. Pharmacological approaches using low dose of DNMT1 inhibitors and combination therapies with current chemotherapy and radiation schemes, have been shown to revert malignant cells to less aggressive states through epigenetic reprogramming, enhancing therapeutic efficacy of conventional treatment. Herein, we describe the functional role of DNMT1 in gliomas, highlighting the underlying molecular mechanisms for effective targeting and tissue delivery approaches to enable future personalized treatment of glioma patients.