Evidence map›Paper›PMID 33795785›Full record

ArticleScientific reports2021

Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression.

Sara Busacca, Qi Zhang, Annabel Sharkey, Alan G Dawson, David A Moore, David A Waller, Apostolos Nakas, Carolyn Jones, Kelvin Cain, Jin-Li Luo and 8 more

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

Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
0.3field-weighted citation impact, top 45% 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

5 citing papers in PubMed, 5 citations in OpenAlex.

  1. Review
  2. Review
  3. Review
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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

18 authors at 12 institutions in 6 countries.

Sara BusaccaLeicester Cancer Research Centre, University of Leicester, Leicester, UK.
Qi ZhangChongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, China.
Annabel SharkeyLeicester Cancer Research Centre, University of Leicester, Leicester, UK.
Alan G DawsonLeicester Cancer Research Centre, University of Leicester, Leicester, UK.
David A MooreCancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
David A WallerDepartment of Thoracic Surgery, St. Bartholomew's Hospital, London, UK.
Apostolos NakasDepartment of Thoracic Surgery, Glenfield Hospital, University Hospitals of Leicester, Leicester, UK.
Carolyn JonesMRC Toxicology Unit, University of Cambridge, Leicester, UK.
Kelvin CainMRC Toxicology Unit, University of Cambridge, Leicester, UK.
Jin-Li LuoLeicester Cancer Research Centre, University of Leicester, Leicester, UK.
Adriana SalcedoDepartments of Human Genetics and Urology, Jonsson Comprehensive Cancer Center and Institute for Precision Health, University of California, Los Angeles, USA.
Iris Chiara SalaroglioDepartment of Oncology, University of Torino, Torino, Italy.
Chiara RigantiDepartment of Oncology, University of Torino, Torino, Italy.
John Le QuesneLeicester Cancer Research Centre, University of Leicester, Leicester, UK.
Tom JohnPeter MacCallum Cancer Centre, Melbourne, Australia.
Paul C BoutrosDepartments of Human Genetics and Urology, Jonsson Comprehensive Cancer Center and Institute for Precision Health, University of California, Los Angeles, USA.
Shu-Dong ZhangNorthern Ireland Centre for Stratified Medicine, School of Biomedical Sciences, Ulster University, Londonderry, UK.
Dean A FennellLeicester Cancer Research Centre, University of Leicester, Leicester, UK. df132@le.ac.uk.
University of Leicester · GBGlenfield Hospital · GBUniversity of Cambridge · GBUniversity of Turin · ITCancer Research UK · GBChongqing Cancer Hospital · CNMRC Toxicology Unit · GBPeter MacCallum Cancer Centre · AUSt Bartholomew's Hospital · GBUniversity of California, Los Angeles · USUniversity of Toronto · CAUniversity of Ulster · GB

Funding

UCLA SPORE in Brain CancerP50CA211015 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Yvonne Yu-Hsuan Chen · 2017 to 2026
$25.2M
Medical Research Council MC_UP_1203/1NCI NIH HHS P50 CA211015
6 · The paper itself

Abstract

We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.

Indexed as

Gene Expression Regulation, NeoplasticBiomarkers, TumorCell Transformation, NeoplasticGene DeletionGene SilencingHumansKaplan-Meier EstimateMesothelioma, MalignantPrognosisProtein-Arginine N-MethyltransferasesProto-Oncogene Proteins c-junPurine-Nucleoside PhosphorylaseQuinacrineTranscription, Genetic5'-methylthioadenosine phosphorylaseBiomarkers, TumorPRMT5 protein, humanProtein-Arginine N-MethyltransferasesProto-Oncogene Proteins c-junPurine-Nucleoside PhosphorylaseQuinacrine

Identifiers

PMID33795785
PMCPMC8016828
OpenAlexW3141084815

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.