Evidence map›Paper›PMID 34772733›Full record

ArticleCancer discovery2022

EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma.

Adam D Durbin, Tingjian Wang, Virangika K Wimalasena, Mark W Zimmerman, Deyao Li, Neekesh V Dharia, Luca Mariani, Noha A M Shendy, Stephanie Nance, Anand G Patel and 19 more

Open access · bronzeAbstract read
In one paragraph

Article in Cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 101 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
101citing papers in PubMed, 2 pooled it
11.9field-weighted citation impact, top 1% 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

101 citing papers in PubMed, 2 syntheses or guidelines pooled it, 152 citations in OpenAlex.

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41 more citing papers are in PubMed but not listed here.

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

29 authors at 8 institutions in 1 country.

Adam D Durbin *Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-5472-9847
Tingjian Wang *Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0003-2203-9590
Virangika K WimalasenaDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-1061-3439
Mark W ZimmermanDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Deyao LiDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0003-2980-3483
Neekesh V DhariaDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0001-5048-067X
Luca MarianiDivision of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-3502-7364
Noha A M ShendyDivision of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Stephanie NanceDivision of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Anand G PatelDepartment of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0002-1438-8275
Ying ShaoDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0002-0390-3315
Maya MundadaDivision of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Lily MaxhamDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Paul M C ParkDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-9380-8548
Logan H SiguaDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Ken MoritaDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Amy Saur ConwayDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Amanda L RobichaudDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Antonio R Perez-AtaydeDepartment of Pathology, Boston Children's Hospital, Boston, Massachusetts.
Melissa J BikowitzDrug Discovery Department, Moffit Cancer Center, Tampa, Florida.
Taylor R QuinnDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana.
Olaf WiestDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana.ORCID 0000-0001-9316-7720
John EastonDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Ernst SchönbrunnDrug Discovery Department, Moffit Cancer Center, Tampa, Florida.
Martha L BulykThe Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Brian J AbrahamDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0001-8085-3027
Kimberly StegmaierDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
A Thomas LookDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0001-7851-8617
Jun QiDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-1461-3356
Dana-Farber Cancer Institute · USSt. Jude Children's Research Hospital · USBroad Institute · USBoston Children's Hospital · USUniversity of Notre Dame · USUniversity of South Florida · USBrigham and Women's Hospital · USHarvard University · US

Funding

Viral Vector Technology (VVTSR)P30CA021765 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI CHARLES ROBERTS · 1985 to 2026
$166.9M
TYROSINE KINASE ONCOGENESIS IN MYELOID LEUKEMIAP01CA066996 · NCI · DANA-FARBER CANCER INSTITUTE · PI SCOTT A ARMSTRONG · 1996 to 2026
$52.5M
Tumor microenvironment-dependent therapy resistanceP01CA217959 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI JOHN M MARIS · 2017 to 2026
$20.7M
Targeting SYK Kinase in AMLP50CA206963 · NCI · DANA-FARBER CANCER INST · PI STEGMAIER, KIMBERLY · 2017 to 2021
$10.6M
PROFESSIONAL ONCOLOGY EDUCATION PROGRAMR25CA023944 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI SUZANNE A. GRONEMEYER · 1986 to 2026
$8.3M
Research Training in Pediatric OncologyT32CA136432 · NCI · DANA-FARBER CANCER INST · PI SCOTT A ARMSTRONG · 2009 to 2026
$7.9M
Integrating Transforming Approaches to Identify and Target New Vulnerabilities in CancerR35CA210030 · NCI · DANA-FARBER CANCER INST · PI STEGMAIER, KIMBERLY · 2016 to 2022
$7.3M
Mechanisms and Vulnerabilities of Aberrant Transcriptional Enhancers in CancerR35CA210064 · NCI · DANA-FARBER CANCER INST · PI LOOK, A. THOMAS · 2016 to 2022
$7.3M
Impact of Coding Variation on Transcription Factor - DNA Recognition_Diversity SupplementR01HG010501 · NHGRI · BRIGHAM AND WOMEN'S HOSPITAL · PI MARTHA L BULYK · 2019 to 2026
$6.9M
Targeting BET-bromodomains in neuroblastomaR01NS088355 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI STEGMAIER, KIMBERLY, WEISS, WILLIAM A · 2015 to 2019
$3.3M
Surveying transcription factor pioneer interactions with nucleosomal DNAR21HG009268 · NHGRI · BRIGHAM AND WOMEN'S HOSPITAL · PI BULYK, MARTHA L · 2016 to 2019
$1.4M
Targeting EP300, a selective dependency in neuroblastomaK08CA245251 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI DURBIN, ADAM DAVID · 2020 to 2024
$1.3M
Damon Runyon Cancer Research Foundation DRSG-24-18NCI NIH HHS K08 CA245251NCI NIH HHS P01 CA066996NCI NIH HHS P01 CA217959NCI NIH HHS P30 CA021765NCI NIH HHS P50 CA206963NCI NIH HHS R25 CA023944NCI NIH HHS R35 CA210030NCI NIH HHS R35 CA210064NCI NIH HHS T32 CA136432NHGRI NIH HHS R01 HG010501NHGRI NIH HHS R21 HG009268NINDS NIH HHS R01 NS088355
6 · The paper itself

Abstract

Gene expression is regulated by promoters and enhancers marked by histone H3 lysine 27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HAT) EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeting chimera (PROTAC) compound termed "JQAD1" that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid NB apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Furthermore, JQAD1 activity is critically determined by cereblon (CRBN) expression across NB cells. SIGNIFICANCE: EP300, but not CBP, controls oncogenic CRC-driven transcription in high-risk NB by binding TFAP2β. We developed JQAD1, a CRBN-dependent PROTAC degrader with preferential activity against EP300 and demonstrated its activity in NB. JQAD1 has limited toxicity to untransformed cells and is effective in vivo in a CRBN-dependent manner. This article is highlighted in the In This Issue feature, p. 587.

Indexed as

NeuroblastomaRegulatory Sequences, Nucleic AcidAcetylationChildE1A-Associated p300 ProteinHumansN-Myc Proto-Oncogene ProteinOncogenesE1A-Associated p300 ProteinEP300 protein, humanMYCN protein, humanN-Myc Proto-Oncogene Protein

Identifiers

PMID34772733
PMCPMC8904277
OpenAlexW3211820355

What OpenQuestion holds

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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.