Long-range gene regulation network of the MGMT enhancer in modulating glioma cell sensitivity to temozolomide

Abstract

Acquired resistance to temozolomide (TMZ) is a major obstacle in glioblastoma treatment. MGMT, a DNA repair protein, and the methylation at its gene promoter, plays an important role in TMZ resistance. However, some evidences have suggested a MGMT-independent mechanisms underlying TMZ resistance. Here, we used MGMT enhancer as a model and discovered that its deletion in glioma cells of low MGMT expression induced increased sensitivity to temozolomide. Analysis of a combination of RNA-seq and Capture Hi-C further suggested multiple long-range target genes regulated by the MGMT enhancer and that interactions may play important roles in glioma cell sensitivity to TMZ. This study reveals a novel mechanism of regulation of TMZ sensitivity in glioma cells.