BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network

Xueqin Sun, Olaf Klingbeil, Bin Lu, Caizhi Wu, Carlos Ballon, Meng Ouyang, Xiaoli S. Wu, Ying Jin, Yon Hwangbo, Yu-Han Huang, Tim D. D. Somerville, Kenneth Chang, Jung Park, Taemoon Chung, Scott K. Lyons, Junwei Shi, Hannes Vogel, Michael Schulder, Christopher R. Vakoc and Alea A. Mills ()
Additional contact information
Xueqin Sun: Cold Spring Harbor Laboratory
Olaf Klingbeil: Cold Spring Harbor Laboratory
Bin Lu: Cold Spring Harbor Laboratory
Caizhi Wu: Cold Spring Harbor Laboratory
Carlos Ballon: Cold Spring Harbor Laboratory
Meng Ouyang: Cold Spring Harbor Laboratory
Xiaoli S. Wu: Cold Spring Harbor Laboratory
Ying Jin: Cold Spring Harbor Laboratory
Yon Hwangbo: Cold Spring Harbor Laboratory
Yu-Han Huang: Cold Spring Harbor Laboratory
Tim D. D. Somerville: Cold Spring Harbor Laboratory
Kenneth Chang: Cold Spring Harbor Laboratory
Jung Park: Zucker School of Medicine at Hofstra Northwell
Taemoon Chung: Cold Spring Harbor Laboratory
Scott K. Lyons: Cold Spring Harbor Laboratory
Junwei Shi: University of Pennsylvania
Hannes Vogel: Department of Pathology, Stanford University
Michael Schulder: Zucker School of Medicine at Hofstra Northwell
Christopher R. Vakoc: Cold Spring Harbor Laboratory
Alea A. Mills: Cold Spring Harbor Laboratory

Nature, 2023, vol. 613, issue 7942, 195-202

Abstract: Abstract Inhibition of the tumour suppressive function of p53 (encoded by TP53) is paramount for cancer development in humans. However, p53 remains unmutated in the majority of cases of glioblastoma (GBM)—the most common and deadly adult brain malignancy1,2. Thus, how p53-mediated tumour suppression is countered in TP53 wild-type (TP53WT) GBM is unknown. Here we describe a GBM-specific epigenetic mechanism in which the chromatin regulator bromodomain-containing protein 8 (BRD8) maintains H2AZ occupancy at p53 target loci through the EP400 histone acetyltransferase complex. This mechanism causes a repressive chromatin state that prevents transactivation by p53 and sustains proliferation. Notably, targeting the bromodomain of BRD8 displaces H2AZ, enhances chromatin accessibility and engages p53 transactivation. This in turn enforces cell cycle arrest and tumour suppression in TP53WT GBM. In line with these findings, BRD8 is highly expressed with H2AZ in proliferating single cells of patient-derived GBM, and is inversely correlated with CDKN1A, a canonical p53 target that encodes p21 (refs. 3,4). This work identifies BRD8 as a selective epigenetic vulnerability for a malignancy for which treatment has not improved for decades. Moreover, targeting the bromodomain of BRD8 may be a promising therapeutic strategy for patients with TP53WT GBM.

Date: 2023
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-022-05551-x Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:613:y:2023:i:7942:d:10.1038_s41586-022-05551-x

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-05551-x

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().