2. Academic Validation
  3. Feedforward miR-181d degradation modulates population variance of methyl-guanine methyl transferase and temozolomide resistance

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

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.

Figures
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