Sun, Xueqin, Klingbeil, Olaf, Lu, Bin, Wu, Caizhi, Ballon, Carlos, Ouyang, Meng, Wu, Xiaoli S, Jin, Ying, Hwangbo, Yon, Huang, Yu-Han, Somerville, Tim DD, Chang, Kenneth, Park, Jung, Chung, Taemoon, Lyons, Scott K, Shi, Junwei, Vogel, Hannes, Schulder, Michael, Vakoc, Christopher R, Mills, Alea A (December 2022) BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network. Nature. ISSN 0028-0836
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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders > cancer > cancer types > glioblastoma bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53 |
| CSHL Authors: | |
| Communities: | CSHL labs > Chang lab CSHL labs > Hammell M. lab CSHL labs > Lyons lab CSHL labs > Mills lab CSHL labs > Stillman lab CSHL labs > Vakoc lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 21 December 2022 |
| Date Deposited: | 22 Dec 2022 15:53 |
| Last Modified: | 22 Dec 2022 15:53 |
| URI: | https://repository.cshl.edu/id/eprint/40775 |
Actions (login required)
 |
Administrator's edit/view item |
