Feedforward miR-181d degradation modulates population variance of methyl-guanine methyl transferase and temozolomide resistance

Intratumoral heterogeneity plays a pivotal role in cancer evolution, providing the substrate for adaptation to selective pressures, including chemotherapy treatment. Here, we demonstrate that miR-181d modulates variability in methyl-guanine methyl transferase (MGMT) expression, contributing to this heterogeneity in glioblastoma, the most common form of adult primary brain tumor. Treatment with standard-of-care temozolomide (TMZ) chemotherapy triggers a feedforward loop that accelerates polyribonucleotide nucleotidyltransferase 1 (PNPT1)-dependent miR-181d degradation. This degradation requires the activation of ataxia-telangiectasia and Rad3-related (ATR) kinase. The degradation of miR-181d in glioblastoma cells increases the variance of MGMT expression in the cell population, contributing to acquired TMZ resistance. This resistance is suppressed by exogenously transfected miR-181d. These findings suggest that microRNA regulates intratumoral heterogeneity by modulating the transcriptional variability of key DNA repair enzymes, providing a compelling rationale for miRNA delivery as a platform for glioblastoma therapy.