EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma

Overview

Journal Cancer Discov

Specialty Oncology

Date 2021 Nov 13

PMID 34772733

Citations 55

Authors

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

Ying Shao

Maya Mundada

Lily Maxham

Paul M C Park

Logan H Sigua

Ken Morita

Amy Saur Conway

Amanda L Robichaud

Antonio R Perez-Atayde

Melissa J Bikowitz

Taylor R Quinn

Olaf Wiest

John Easton

Ernst Schonbrunn

Martha L Bulyk

Brian J Abraham

Kimberly Stegmaier

A Thomas Look

Jun Qi

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Dysregulation of the p300/CBP histone acetyltransferases in human cancer.

Xu L, Xuan H, Shi X Epigenomics. 2025; 17(3):193-208.

PMID: 39929233 PMC: 11812348. DOI: 10.1080/17501911.2024.2447807.

The important role of the histone acetyltransferases p300/CBP in cancer and the promising anticancer effects of p300/CBP inhibitors.

Wu X, Zhang X, Tang S, Wang Y Cell Biol Toxicol. 2025; 41(1):32.

PMID: 39825161 PMC: 11742294. DOI: 10.1007/s10565-024-09984-0.

Validation and the role of PDK4 relevant to ferroptosis in degenerative lumbar disc disease.

Chen W, Yang W, Meng B, Wang X, Duan H, Xu Q J Orthop Surg Res. 2025; 20(1):30.

PMID: 39794775 PMC: 11724506. DOI: 10.1186/s13018-024-05293-8.

Progress Toward Epigenetic Targeted Therapies for Childhood Cancer.

Liapodimitri A, Tetens A, Craig-Schwartz J, Lunsford K, Skalitzky K, Koldobskiy M Cancers (Basel). 2025; 16(24.

PMID: 39766049 PMC: 11674401. DOI: 10.3390/cancers16244149.

Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.

Likasitwatanakul P, Li Z, Doan P, Spisak S, Raghawan A, Liu Q bioRxiv. 2024; .

PMID: 39713466 PMC: 11661112. DOI: 10.1101/2024.12.06.626451.

References

Wang L, Tan T, Durbin A, Zimmerman M, Abraham B, Tan S . ASCL1 is a MYCN- and LMO1-dependent member of the adrenergic neuroblastoma core regulatory circuitry. Nat Commun. 2019; 10(1):5622. PMC: 6901540. DOI: 10.1038/s41467-019-13515-5. View

Mi H, Muruganujan A, Casagrande J, Thomas P . Large-scale gene function analysis with the PANTHER classification system. Nat Protoc. 2013; 8(8):1551-66. PMC: 6519453. DOI: 10.1038/nprot.2013.092. View

Tate E, Wilder M, Cram L, Wharton W . A method for staining 3T3 cell nuclei with propidium iodide in hypotonic solution. Cytometry. 1983; 4(3):211-5. DOI: 10.1002/cyto.990040304. View

. Gene Ontology Consortium: going forward. Nucleic Acids Res. 2014; 43(Database issue):D1049-56. PMC: 4383973. DOI: 10.1093/nar/gku1179. View

Yasgar A, Jadhav A, Simeonov A, Coussens N . AlphaScreen-Based Assays: Ultra-High-Throughput Screening for Small-Molecule Inhibitors of Challenging Enzymes and Protein-Protein Interactions. Methods Mol Biol. 2016; 1439:77-98. PMC: 5444910. DOI: 10.1007/978-1-4939-3673-1_5. View

Durbin A, Zimmerman M, Dharia N, Abraham B, Iniguez A, Weichert-Leahey N . Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry. Nat Genet. 2018; 50(9):1240-1246. PMC: 6386470. DOI: 10.1038/s41588-018-0191-z. View

Kasper L, Fukuyama T, Biesen M, Boussouar F, Tong C, de Pauw A . Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development. Mol Cell Biol. 2006; 26(3):789-809. PMC: 1347027. DOI: 10.1128/MCB.26.3.789-809.2006. View

Wimalasena V, Wang T, Sigua L, Durbin A, Qi J . Using Chemical Epigenetics to Target Cancer. Mol Cell. 2020; 78(6):1086-1095. PMC: 8033568. DOI: 10.1016/j.molcel.2020.04.023. View

Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W . c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell. 2012; 151(1):68-79. PMC: 3471363. DOI: 10.1016/j.cell.2012.08.033. View

10.

Zhang K, Faiola F, Martinez E . Six lysine residues on c-Myc are direct substrates for acetylation by p300. Biochem Biophys Res Commun. 2005; 336(1):274-80. DOI: 10.1016/j.bbrc.2005.08.075. View

11.

Ghandi M, Huang F, Jane-Valbuena J, Kryukov G, Lo C, McDonald 3rd E . Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature. 2019; 569(7757):503-508. PMC: 6697103. DOI: 10.1038/s41586-019-1186-3. View

12.

Suzuki H, Young R, Sharp P . Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis. Cell. 2017; 168(6):1000-1014.e15. PMC: 5350633. DOI: 10.1016/j.cell.2017.02.015. View

13.

Parker S, Stitzel M, Taylor D, Orozco J, Erdos M, Akiyama J . Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc Natl Acad Sci U S A. 2013; 110(44):17921-6. PMC: 3816444. DOI: 10.1073/pnas.1317023110. View

14.

Martire S, Nguyen J, Sundaresan A, Banaszynski L . Differential contribution of p300 and CBP to regulatory element acetylation in mESCs. BMC Mol Cell Biol. 2020; 21(1):55. PMC: 7370441. DOI: 10.1186/s12860-020-00296-9. View

15.

Huang M, Weiss W . Neuroblastoma and MYCN. Cold Spring Harb Perspect Med. 2013; 3(10):a014415. PMC: 3784814. DOI: 10.1101/cshperspect.a014415. View

16.

Yao T, P Oh S, Fuchs M, Zhou N, ChNg L, Newsome D . Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell. 1998; 93(3):361-72. DOI: 10.1016/s0092-8674(00)81165-4. View

17.

Vannam R, Sayilgan J, Ojeda S, Karakyriakou B, Hu E, Kreuzer J . Targeted degradation of the enhancer lysine acetyltransferases CBP and p300. Cell Chem Biol. 2021; 28(4):503-514.e12. DOI: 10.1016/j.chembiol.2020.12.004. View

18.

Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin A, Kim S . The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012; 483(7391):603-7. PMC: 3320027. DOI: 10.1038/nature11003. View

19.

Boeva V, Louis-Brennetot C, Peltier A, Durand S, Pierre-Eugene C, Raynal V . Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries. Nat Genet. 2017; 49(9):1408-1413. DOI: 10.1038/ng.3921. View

20.

Sabari B, DallAgnese A, Boija A, Klein I, Coffey E, Shrinivas K . Coactivator condensation at super-enhancers links phase separation and gene control. Science. 2018; 361(6400). PMC: 6092193. DOI: 10.1126/science.aar3958. View