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

  • Cell Rep. 2025 Nov 25;44(11):116516. doi: 10.1016/j.celrep.2025.116516.
Gatikrushna Singh  1 ,  Shilpi Singh  2 ,  Iteeshree Mohapatra  3 ,  Stefan Kim  2 ,  Mayur Sharma  2 ,  Johnny Akers  4 ,  Thien Nguyen  5 ,  Eric Wong  6 ,  Margot Martinez Moreno  7 ,  Efrosini Kokkoli  8 ,  Shobha Vasudevan  9 ,  Sean E Lawler  10 ,  Wafik S El-Deiry  10 ,  Ziya Gokaslan  7 ,  Clark C Chen  7
Affiliations
  • 1. Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: [email protected].
  • 2. Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA.
  • 3. Department of Veterinary Biomedical Sciences, St. Paul, MN 55108, USA.
  • 4. VisiCELL Medical Inc., San Diego, CA 92121, USA.
  • 5. Department of Pediatrics, Stanford University, Stanford, CA 94304, USA.
  • 6. Department of Neurology, Warren Alpert School of Medicine, Rhode Island Hospital, Brown University, Providence, RI 02903, USA.
  • 7. Department of Neurosurgery, Warren Alpert School of Medicine, Rhode Island Hospital, Brown University, Providence, RI 02903, USA.
  • 8. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
  • 9. Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02903, USA.
  • 10. Department of Pathology and Laboratory Medicine, Legorreta Cancer Center, Brown University, Providence, RI 02903, USA.
PMID: 41217933 DOI: 10.1016/j.celrep.2025.116516
Abstract

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.

Keywords
ATR; CP: cancer; MGMT; PNPT1; glioblastoma; microRNA; temozolomide.
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