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

SUMMARY 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.

• Publication year

  2025

• Venue

  Cell Reports

• Publication date

  2025-11-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.celrep.2025.116516PMID 41217933PMCID 12767607
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Glioblastoma at the crossroads: current understanding and future therapeutic horizons

  2025cited by this paper
• What single-cell RNA sequencing taught us about MGMT expression in glioblastoma

  2025cited by this paper
• Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics

  2025cited by this paper
• To kill a microRNA: emerging concepts in target-directed microRNA degradation

  2024cited by this paper
• Role of Extracellular vesicle microRNAs and RNA binding proteins on glioblastoma dynamics and therapeutics development

  2024cited by this paper
• Transcriptional bursting dynamics in gene expression

  2024cited by this paper
• Target‐directed microRNA degradation: Mechanisms, significance, and functional implications

  2024cited by this paper
• Integrated analysis of single-cell chromatin state and transcriptome identified common vulnerability despite glioblastoma heterogeneity

  2023cited by this paper
• Purification and characterization of human neural stem and progenitor cells.

  2023cited by this paper
• An overview of glioblastoma multiforme and temozolomide resistance: can LC-MS-based proteomics reveal the fundamental mechanism of temozolomide resistance?

  2023cited by this paper
• Characterizing the landscape of gene expression variance in humans

  2023cited by this paper
• SnapShot: Target-directed miRNA degradation.

  2023cited by this paper
• Recent progress in miRNA biogenesis and decay

  2023cited by this paper
• Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.

  2023cited by this paper
• The effect of microRNA on protein variability and gene expression fidelity.

  2023cited by this paper
• The ATR inhibitor VE-821 increases the sensitivity of gastric cancer cells to cisplatin

  2023cited by this paper
• The Role of MicroRNA in DNA Damage Response

  2022cited by this paper
• Activity and Function in Human Cells of the Evolutionary Conserved Exonuclease Polynucleotide Phosphorylase

  2022cited by this paper
• Bursting Translation on Single mRNAs in Live Cells

  2022cited by this paper
• Variant interpretation using population databases: Lessons from gnomAD

  2021cited by this paper
• miRge3.0: a comprehensive microRNA and tRF sequencing analysis pipeline

  2021cited by this paper
• The promise of DNA damage response inhibitors for the treatment of glioblastoma

  2021cited by this paper
• MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

  2020cited by this paper
• Radiation-induced extracellular vesicle (EV) release of miR-603 promotes IGF1-mediated stem cell state in glioblastomas

  2020cited by this paper
• O6-Methylguanine-DNA Methyltransferase (MGMT): Challenges and New Opportunities in Glioma Chemotherapy

  2020cited by this paper
• Temozolomide sensitizes MGMT-deficient tumor cells to ATR inhibitors.

  2019cited by this paper
• Illustrating the importance of meta‐analysing variances alongside means in ecology and evolution

  2019cited by this paper
• mRNA Stability Assay Using transcription inhibition by Actinomycin D in Mouse Pluripotent Stem Cells.

  2018cited by this paper
• Stochastic tuning of gene expression enables cellular adaptation in the absence of pre-existing regulatory circuitry

  2018cited by this paper
• PNPT1 Release from Mitochondria during Apoptosis Triggers Decay of Poly(A) RNAs.

  2018cited by this paper
• Mitochondrial double-stranded RNA triggers antiviral signalling in humans

  2018cited by this paper
• A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma

  2018cited by this paper
• Crystal structure of dimeric human PNPase reveals why disease-linked mutants suffer from low RNA import and degradation activities

  2018cited by this paper
• Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation

  2018cited by this paper
• Investigating Neural Stem Cell and Glioma Stem Cell Self-renewal Potential Using Extreme Limiting Dilution Analysis (ELDA).

  2018cited by this paper
• Major 3'-5' Exoribonucleases in the Metabolism of Coding and Non-coding RNA.

  2018cited by this paper
• Post-transcriptional control of miRNA biogenesis

  2018cited by this paper
• Immunohistochemical Evaluation of Aquaporin-4 and its Correlation with CD68, IBA-1, HIF-1α, GFAP, and CD15 Expressions in Fatal Traumatic Brain Injury

  2018cited by this paper
• miRTrace reveals the organismal origins of microRNA sequencing data

  2018cited by this paper
• MirGeneDB 2.0: the metazoan microRNA complement

  2018cited by this paper
• The impact of microRNAs on transcriptional heterogeneity and gene co-expression across single embryonic stem cells

  2017cited by this paper
• miRNA array screening reveals cooperative MGMT-regulation between miR-181d-5p and miR-409-3p in glioblastoma

  2016cited by this paper
• Highly variable cancer subpopulations that exhibit enhanced transcriptome variability and metastatic fitness

  2016cited by this paper
• microRNA Therapeutics in Cancer — An Emerging Concept

  2016cited by this paper
• Stochastic activation of a DNA damage response causes cell-to-cell mutation rate variation

  2016cited by this paper
• RNA Sequencing and Analysis.

  2015cited by this paper
• Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression

  2015cited by this paper
• Prognosis of glioblastoma with faint MGMT methylation-specific PCR product

  2015cited by this paper
• MicroRNA control of protein expression noise

  2015cited by this paper
• New insights into the mechanism of DNA mismatch repair

  2015cited by this paper
• A genome-wide miRNA screen revealed miR-603 as a MGMT-regulating miRNA in glioblastomas

  2014cited by this paper
• Targeting ATR in DNA damage response and cancer therapeutics.

  2014cited by this paper
• miR-21 in the Extracellular Vesicles (EVs) of Cerebrospinal Fluid (CSF): A Platform for Glioblastoma Biomarker Development

  2013cited by this paper
• O6-methylguanine DNA methyltransferase as a promising target for the treatment of temozolomide-resistant gliomas

  2013cited by this paper
• Roles for microRNAs in conferring robustness to biological processes.

  2012cited by this paper
• Crosstalk between the DNA damage response pathway and microRNAs

  2012cited by this paper
• Impact of microRNA regulation on variation in human gene expression

  2012cited by this paper
• MicroRNA degradation and turnover: regulating the regulators

  2012cited by this paper
• miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression.

  2012cited by this paper
• MiR-181d acts as a tumor suppressor in glioma by targeting K-ras and Bcl-2

  2012cited by this paper
• PNPASE and RNA trafficking into mitochondria.

  2012cited by this paper
• O6-Methylguanine DNA lesions induce an intra-S-phase arrest from which cells exit into apoptosis governed by early and late multi-pathway signaling network activation.

  2012cited by this paper
• Post-transcriptional regulation of O6-methylguanine-DNA methyltransferase MGMT in glioblastomas

  2011cited by this paper
• Multifaceted roles of alkyltransferase and related proteins in DNA repair, DNA damage, resistance to chemotherapy, and research tools.

  2011cited by this paper
• Human polynucleotide phosphorylase selectively and preferentially degrades microRNA-221 in human melanoma cells

  2010cited by this paper
• PNPASE regulates RNA import into mitochondria.

  2010cited by this paper
• Changes of the O6-methylguanine-DNA methyltransferase promoter methylation and MGMT protein expression after adjuvant treatment in glioblastoma.

  2010cited by this paper
• Target RNA–Directed Trimming and Tailing of Small Silencing RNAs

  2010cited by this paper
• Mechanisms of control of microRNA biogenesis.

  2010cited by this paper
• Making RISC.

  2010cited by this paper
• Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts.

  2009cited by this paper
• Drosophila argonaute1 and argonaute2 employ distinct mechanisms for translational repression.

  2009cited by this paper
• Comprehensive genomic characterization defines human glioblastoma genes and core pathways

  2008cited by this paper
• Mismatch repair proteins collaborate with methyltransferases in the repair of O(6)-methylguanine.

  2008cited by this paper
• Crystal structure of Escherichia coli PNPase: central channel residues are involved in processive RNA degradation.

  2008cited by this paper
• Human variants of O6-alkylguanine-DNA alkyltransferase.

  2007cited by this paper
• MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents.

  2007cited by this paper
• Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.

  2005cited by this paper
• MicroRNAs: small RNAs with a big role in gene regulation

  2004cited by this paper
• Repair of O6-alkylguanine by alkyltransferases

  2000cited by this paper
• Repair of O(6)-alkylguanine by alkyltransferases.

  2000cited by this paper
• The Transcriptional Inhibitors, Actinomycin D and α-Amanitin, Activate the HIV-1 Promoter and Favor Phosphorylation of the RNA Polymerase II C-terminal Domain*

  1999cited by this paper
• Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents.

  1990cited by this paper

• No citing papers are available for this paper.