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Decitabine Reprograms Temozolomide-Resistant Glioblastoma Through Epigenetic Reactivation and Mesenchymal Attenuation: A Multi-Omics Study.

Overview

Authors: Itika Arora1, Shamsa Hilal Saleh1, Arshiya Akbar1, Fareeha Arshad1, Volodymyr Mavrych1, Olena Bolgova1, Faisal Abdulhameed Farrash2, Ahmed Abu-Zaid1, Andleeb Khan3,4, Sheikh Muskan3,4, Mohammed Imran Khan5, Ahmed Yaqinuddin1
  1. College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
  2. King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 12713, Saudi Arabia
  3. Department of Biosciences, Faculty of Science, Integral University, Lucknow 226026, India
  4. Stem Cell Biology Lab, Integral Center of Excellence for Interdisciplinary Research-4 (ICEIR-12), Integral University, Lucknow 226026, India
  5. King Faisal Specialist Hospital and Research Centre (KFSHRC), Jeddah 23433, Saudi Arabia
Journal: Cancers, volume 18, issue 16, article 2616
Dates: received 13 July 2026; accepted 5 August 2026; published online 14 August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.3390/cancers18162616 · PMID 42649932 · PMCID PMC13511076 · OpenAlex W7203440715
Open access: gold, a free copy (OpenAlex)
Status: code on request
Categories: genetics / omics (modality), human (organism), other condition (population)
Methods: Connectivity, Statistics, Smoothing, state filtering, decompositions, Machine learning, Preprocessing
Keywords: temozolomide resistance, decitabine, epigenetic de-repression, INPP5D/SHIP1, PI3K–AKT signaling, multi-omics integration, single-cell transcriptomics, TCGA-GBM survival, pharmacogenomics, interferon response, mesenchymal transition
Topic: Glioma Diagnosis and Treatment (Genetics, Medicine), according to OpenAlex
Funding: Alfaisal University (IRG# 25345)
Citations: not cited yet (Europe PMC); 48 references in the paper

Abstract

Background/Objectives: Glioblastoma (GBM) is the most lethal primary brain malignancy in adults, with a median overall survival of approximately 15 months. Temozolomide (TMZ) resistance develops in virtually all patients, and no second-line regimen has improved outcomes over the past two decades. The DNA methyltransferase inhibitor decitabine (DAC) has attracted interest as a chemosensitizer, but whether it directly reverses the TMZ-resistance transcriptome or operates through distinct, complementary mechanisms has not been tested at multi-omics resolution. Methods: We performed an integrative six-layer multi-omics analysis across five public GEO datasets (bulk RNA-seq, EPIC 850K methylation, and 21,676 single cells) re-purposed from studies conducted for unrelated aims, formally tested DAC-mediated reversal of the TMZ-resistance transcriptome across 11,707 genes, mapped pharmacogenomic targets with DGIdb v5, and built an exploratory, hypothesis-generating 11-gene prognostic model internally validated in TCGA-GBM (n = 166) and externally tested in the independent CPTAC-GBM cohort (n = 96). Results: DAC reprogrammed transcription across 1114–1882 differentially expressed genes per cohort and reactivated 146 direct epigenetic targets, identifying INPP5D/SHIP1 as the top-ranked direct epigenetic-reactivation target. Genome-wide reversal analysis across 11,707 co-detected genes showed a negligible effect (Spearman ρ = 0.073), but single-cell analysis revealed significant per-cell attenuation of MES-like and stem-like programs (Δ = −0.071 and −0.135, respectively; both p < 0.001). The 11-gene risk model achieved a Harrell’s C-index of 0.706 (apparent); after correcting for the two-stage gene selection with a full-pipeline bootstrap, the optimism-corrected C-index was 0.63, and external validation in an independent cohort (CPTAC-GBM, n = 96) showed only near-chance discrimination (C-index 0.55), indicating that the signature does not generalize and is exploratory. Pharmacogenomic mapping yielded 734 unique therapeutic agents (230 FDA-approved) across 69 druggable targets after excluding AR. Most of these agents are not GBM-directed, so this catalog-level mapping is hypothesis-generating rather than a set of therapeutic recommendations. Conclusions: DAC does not broadly reverse the TMZ-resistant transcriptome but acts through three complementary mechanisms: epigenetic reactivation of INPP5D/SHIP1, cancer-testis-antigen and type I interferon induction, and per-cell attenuation of mesenchymal–stem-like transcriptional intensity, supporting hypotheses for rationally designed DAC-based combination therapy in TMZ-resistant GBM.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

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Data

Datasets cited

Other data links

2.1. Public Datasets and Data Accessibility

All data were sourced from publicly available repositories. The datasets analyzed here are listed below (Table 1):

Raw data were downloaded from Gene Expression Omnibus (GEO [18]; https://www.ncbi.nlm.nih.gov/geo/, accessed on 10 July 2026) using the accession IDs listed above. GSE151680 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151680) was originally generated by Liu et al. [17] to construct and externally validate a ferroptosis-related prognostic gene signature in glioma, and GSE261187 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE261187), GSE261188 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE261188), and GSE261190 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE261190) were originally generated by Lai et al. [16] to characterize DAC-induced cancer testis antigen and endogenous retrovirus reactivation at single-cell resolution; neither prior study analyzed TMZ resistance or tested transcriptional reversal by DAC (see Section 1). TCGA-GBM data were accessed via UCSC Xena (https://xenabrowser.net/, accessed on 10 July 2026). All analyses comply with data usage agreements for publicly available, de-identified data.

Reproduced under the paper's license (CC BY), from the paper cited above.

Data Availability Statement

All data were sourced from publicly available repositories. The datasets analyzed here are listed below (Table 1):

Raw data were downloaded from Gene Expression Omnibus (GEO [18]; https://www.ncbi.nlm.nih.gov/geo/, accessed on 10 July 2026) using the accession IDs listed above. GSE151680 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151680) was originally generated by Liu et al. [17] to construct and externally validate a ferroptosis-related prognostic gene signature in glioma, and GSE261187 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE261187), GSE261188 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE261188), and GSE261190 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE261190) were originally generated by Lai et al. [16] to characterize DAC-induced cancer testis antigen and endogenous retrovirus reactivation at single-cell resolution; neither prior study analyzed TMZ resistance or tested transcriptional reversal by DAC (see Section 1). TCGA-GBM data were accessed via UCSC Xena (https://xenabrowser.net/, accessed on 10 July 2026). All analyses comply with data usage agreements for publicly available, de-identified data.

The original data presented in the study are openly available in the Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/ (accessed on 10 July 2026) under accessions GSE151680 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151680), GSE261187 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE261187), GSE80137 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE80137), GSE261190 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE261190), and GSE261188 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE261188). TCGA-GBM data are available through the UCSC Xena Browser (https://xenabrowser.net/, accessed on 10 July 2026). All analysis code and processed data tables will be made available on GitHub upon acceptance.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 11 keywords, 1 funder, 47 references.

Cite

This paper

Arora, I., Saleh, S. H., Akbar, A., Arshad, F., Mavrych, V., Bolgova, O., Farrash, F. A., Abu-Zaid, A., Khan, A., Muskan, S., Khan, M. I., & Yaqinuddin, A. (2026). Decitabine Reprograms Temozolomide-Resistant Glioblastoma Through Epigenetic Reactivation and Mesenchymal Attenuation: A Multi-Omics Study. Cancers, 18(16), 2616. https://doi.org/10.3390/cancers18162616

BibTeX

@article{arora2026decitabine,
author = {Arora, Itika and Saleh, Shamsa Hilal and Akbar, Arshiya and Arshad, Fareeha and Mavrych, Volodymyr and Bolgova, Olena and Farrash, Faisal Abdulhameed and Abu-Zaid, Ahmed and Khan, Andleeb and Muskan, Sheikh and Khan, Mohammed Imran and Yaqinuddin, Ahmed},
title = {{Decitabine Reprograms Temozolomide-Resistant Glioblastoma Through Epigenetic Reactivation and Mesenchymal Attenuation: A Multi-Omics Study}},
journal = {Cancers},
year = {2026},
month = aug,
volume = {18},
number = {16},
pages = {2616},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
issn = {2072-6694},
doi = {10.3390/cancers18162616},
url = {https://doi.org/10.3390/cancers18162616},
pmid = {42649932},
pmcid = {PMC13511076}
}

RIS

TY - JOUR
AU - Arora, Itika
AU - Saleh, Shamsa Hilal
AU - Akbar, Arshiya
AU - Arshad, Fareeha
AU - Mavrych, Volodymyr
AU - Bolgova, Olena
AU - Farrash, Faisal Abdulhameed
AU - Abu-Zaid, Ahmed
AU - Khan, Andleeb
AU - Muskan, Sheikh
AU - Khan, Mohammed Imran
AU - Yaqinuddin, Ahmed
TI - Decitabine Reprograms Temozolomide-Resistant Glioblastoma Through Epigenetic Reactivation and Mesenchymal Attenuation: A Multi-Omics Study
T2 - Cancers
J2 - Cancers (Basel)
PY - 2026
DA - 2026/08/14
VL - 18
IS - 16
SP - 2616
SN - 2072-6694
PB - Multidisciplinary Digital Publishing Institute (MDPI)
DO - 10.3390/cancers18162616
UR - https://doi.org/10.3390/cancers18162616
LA - en
ER -

CSL-JSON

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