Evidence map›Paper›PMID 37645799›Full record

ArticlebioRxiv : the preprint server for biology2023

EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes.

Yeying Huang, R Taylor Durall, Nhi M Luong, Hans J Hertzler, Julianna Huang, Prafulla C Gokhale, Brittaney A Leeper, Nicole S Persky, David E Root, Praju V Anekal and 16 more

Open access · greenAbstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
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

1 citing paper in PubMed, 2 citations in OpenAlex.

  1. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

26 authors at 10 institutions in 1 country.

Yeying HuangDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
R Taylor DurallDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nhi M LuongDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Hans J HertzlerDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Julianna HuangDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Prafulla C GokhaleExperimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
Brittaney A LeeperExperimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
Nicole S PerskyBroad Institute of MIT and Harvard, Cambridge, MA, USA.
David E RootBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Praju V AnekalMicRoN, Department of Microbiology, Harvard Medical School, Boston, MA, USA.
Paula D L M Montero LlopisMicRoN, Department of Microbiology, Harvard Medical School, Boston, MA, USA.
Clement N DavidNanoString Technologies, Inc., Seattle, WA, USA.
Jeffery L KutokEpizyme Inc., Cambridge, MA, USA.
Alejandra RaimondiEpizyme Inc., Cambridge, MA, USA.
Karan SalujaDepartment of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, TX, USA.
Jia LuoDepartment of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cynthia A ZahnowDepartment of Oncology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Biniam AdaneDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Kimberly StegmaierDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Catherine E HawkinsDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Christopher PonneDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Quan LeDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Geoffrey I ShapiroDepartment of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Madeleine E LemieuxBioinfo, Plantagenet, ON, Canada.
Kyle P EagenDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Christopher A FrenchDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Brigham and Women's Hospital · USBaylor College of Medicine · USHarvard University · USDana-Farber Cancer Institute · USBroad Institute · USEpizyme (United States) · USBoston Children's Hospital · USJohns Hopkins University · USNanostring Technologies (United States) · USThe University of Texas Health Science Center at Houston · US

Funding

Integrating Transforming Approaches to Identify and Target New Vulnerabilities in CancerR35CA210030 · NCI · DANA-FARBER CANCER INST · PI STEGMAIER, KIMBERLY · 2016 to 2022
$7.3M
Pathogenesis of NUT-Rearranged CarcinomaR01CA124633 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI Christopher A French · 2007 to 2026
$7.0M
Biochemical Basis of Chromatin Folding and Chromosome CondensationDP5OD024587 · OD · NORTHWESTERN UNIVERSITY AT CHICAGO · PI EAGEN, KYLE PATRICK · 2017 to 2021
$2.0M
NCI NIH HHS R01 CA124633NCI NIH HHS R35 CA210030NIH HHS DP5 OD024587
6 · The paper itself

Abstract

NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) impede BRD4-NUT's ability to activate genes and are thus a promising treatment but limited as monotherapy. The role of gene repression in NC is unknown. Here, we demonstrate that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark, and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4- NUT-regulated genes. STATEMENT OF SIGNIFICANCE: Identification of EZH2 as a dependency in NC substantiates the reliance of NC tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary chromatin regulatory pathways to maintain NC growth. In particular, repression of CDKN2A expression by EZH2 provides a mechanistic rationale for combining EZH2i with BETi for the clinical treatment of NC.

Identifiers

PMID37645799
PMCPMC10461970
OpenAlexW4385953139

What OpenQuestion holds

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LicenceCC BY-ND
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Registered trials

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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.