Evidence map›Paper›PMID 37639774›Full record

ArticleDrug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy2023

H3K4me3 remodeling induced acquired resistance through O-GlcNAc transferase.

Dinoop Ravindran Menon, Heinz Hammerlindl, Gregory Gimenez, Sabrina Hammerlindl, Elmar Zuegner, Joachim Torrano, Natalie Bordag, Abdullah Al Emran, Maybelline Giam, Simon Denil and 10 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
1.4field-weighted citation impact, top 19% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed, 9 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors at 8 institutions in 5 countries.

Dinoop Ravindran MenonFrazer Institute, The University of Queensland, Brisbane, QLD, Australia; Department of Dermatology, University of Colorado Denver, Aurora, CO, USA; Department of Medical Oncology, University of Colorado Denver, Aurora, CO, USA.
Heinz HammerlindlFrazer Institute, The University of Queensland, Brisbane, QLD, Australia; Department of Pharmaceutical Chemistry, The University of California, San Francisco, San Francisco, CA, USA.
Gregory GimenezDepartment of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
Sabrina HammerlindlFrazer Institute, The University of Queensland, Brisbane, QLD, Australia; Department of Pharmaceutical Chemistry, The University of California, San Francisco, San Francisco, CA, USA.
Elmar ZuegnerJoanneum Research Forschungsgesellschaft m.b.H., HEALTH, Institute for Biomedicine and Health Sciences, Graz, Austria.
Joachim TorranoFrazer Institute, The University of Queensland, Brisbane, QLD, Australia.
Natalie BordagJoanneum Research Forschungsgesellschaft m.b.H., HEALTH, Institute for Biomedicine and Health Sciences, Graz, Austria.
Abdullah Al EmranFrazer Institute, The University of Queensland, Brisbane, QLD, Australia.
Maybelline GiamInstitute of Medical Biology, Agency for Science, Technology and Research, Immunos Singapore, Singapore.
Simon DenilInstitute of Medical Biology, Agency for Science, Technology and Research, Immunos Singapore, Singapore.
Norman PavelkaSIgN, the Singapore Institute for Immunology, Agency for Science, Technology and Research, Immunos Singapore, Singapore.
Aik-Choon TanDivision of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
Richard A SturmFrazer Institute, The University of Queensland, Brisbane, QLD, Australia.
Nikolas K HaassFrazer Institute, The University of Queensland, Brisbane, QLD, Australia.
Giulia RancatiInstitute of Medical Biology, Agency for Science, Technology and Research, Immunos Singapore, Singapore.
Meenhard HerlynThe Wistar Institute, Philadelphia, PA, USA.
Christoph MagnesJoanneum Research Forschungsgesellschaft m.b.H., HEALTH, Institute for Biomedicine and Health Sciences, Graz, Austria.
Michael R EcclesDepartment of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.
Mayumi FujitaDepartment of Dermatology, University of Colorado Denver, Aurora, CO, USA; Denver VA Medical Center, Denver, CO, USA; Department of Immunology and Microbiology, University of Colorado Denver, Aurora, CO, USA.
Helmut SchaiderFrazer Institute, The University of Queensland, Brisbane, QLD, Australia; Department of Dermatology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia. Electronic address: h.schaider@uq.edu.au.
The University of Queensland · AUAgency for Science, Technology and Research · SGJoanneum Research · ATDenver VA Medical Center · USMaurice Wilkins Centre · NZThe Wistar Institute · USUniversity of Colorado Denver · USUniversity of Otago · NZ

Funding

Tumor Microenvironment and MetastasisP30CA010815 · NCI · WISTAR INSTITUTE · PI Luis J Montaner · 1985 to 2026
$75.9M
Targeting the MAP and PI3 Kinase Pathways in MelanomaP01CA114046 · NCI · WISTAR INSTITUTE · PI HERLYN, MEENHARD F, WEERARATNA, ASHANI T · 2008 to 2023
$37.1M
Modulation of Inflammasome-mediated cytokine activation by EGCG in human melanomaR01CA197919 · NCI · UNIVERSITY OF COLORADO DENVER · PI FUJITA, MAYUMI · 2016 to 2020
$1.9M
Autoinflammation in Human MelanomaI01BX001228 · VA · VA EASTERN COLORADO HEALTH CARE SYSTEM · PI FUJITA, MAYUMI · 2012 to 2022
–
BLRD VA I01 BX001228NCI NIH HHS P01 CA114046NCI NIH HHS P30 CA010815NCI NIH HHS R01 CA197919VA 5I01BX001228
6 · The paper itself

Abstract

aimsDrivers of the drug tolerant proliferative persister (DTPP) state have not been well investigated. Histone H3 lysine-4 trimethylation (H3K4me3), an active histone mark, might enable slow cycling drug tolerant persisters (DTP) to regain proliferative capacity. This study aimed to determine H3K4me3 transcriptionally active sites identifying a key regulator of DTPPs.

methodsDeploying a model of adaptive cancer drug tolerance, H3K4me3 ChIP-Seq data of DTPPs guided identification of top transcription factor binding motifs. These suggested involvement of O-linked N-acetylglucosamine transferase (OGT), which was confirmed by metabolomics analysis and biochemical assays. OGT impact on DTPPs and adaptive resistance was explored in vitro and in vivo.

resultsH3K4me3 remodeling was widespread in CPG island regions and DNA binding motifs associated with O-GlcNAc marked chromatin. Accordingly, we observed an upregulation of OGT, O-GlcNAc and its binding partner TET1 in chronically treated cancer cells. Inhibition of OGT led to loss of H3K4me3 and downregulation of genes contributing to drug resistance. Genetic ablation of OGT prevented acquired drug resistance in in vivo models. Upstream of OGT, we identified AMPK as an actionable target. AMPK activation by acetyl salicylic acid downregulated OGT with similar effects on delaying acquired resistance.

conclusionOur findings uncover a fundamental mechanism of adaptive drug resistance that governs cancer cell reprogramming towards acquired drug resistance, a process that can be exploited to improve response duration and patient outcomes.

Indexed as

AMP-Activated Protein KinasesHistonesDown-RegulationHumansMixed Function OxygenasesN-AcetylglucosaminyltransferasesProto-Oncogene ProteinsAMP-Activated Protein Kinaseshistone H3 trimethyl Lys4HistonesMixed Function OxygenasesN-AcetylglucosaminyltransferasesO-GlcNAc transferaseProto-Oncogene ProteinsTET1 protein, humanAcquired drug resistanceAdaptive cancer drug resistanceCancer persistersCellular reprogrammingEpigeneticsH3K4me3MetabolismOGTTET1

Identifiers

PMID37639774
PMCPMC10719180
OpenAlexW4385739824

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.