BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network

Sun, Xueqin; Klingbeil, Olaf; Lü, Bin; Wu, Caizhi; Ballon, Carlos; Ouyang, Meng; Wu, Xiaoli; Jin, Ying; Hwangbo, Yon; Huang, Yuhan; Somerville, Tim D.D.; Chang, Kenneth; Park, Jung; Chung, Taemoon; Lyons, Scott K.; Shi, Junwei; Vogel, Hannes; Schulder, Michael; Vakoc, Christopher R.; Mills, Alea A.

doi:10.1038/s41586-022-05551-x

Cited by 32 publications

(18 citation statements)

References 62 publications

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“…Importantly, many of the p53-DREAM targets we identified play a role in brain development, suggesting that the impact of a loss or attenuation of the p53-DREAM pathway might be particularly relevant for brain tumorigenesis. In support of this possibility, the chromatin regulator bromodomain-containing protein 8 (BRD8) was recently shown to attenuate p53 in glioblastoma ( Sun et al, 2023 ), and we observed, in glioblastoma cells with high BRD8 levels ( Wu et al, 2020 ), an overall increased expression for the 77 p53-DREAM targets associated with microcephaly or cerebellar hypoplasia ( Fig. 4A ; Table S37 ).…”

Section: Discussionsupporting

confidence: 67%

A systematic approach identifies p53-DREAM pathway target genes associated with blood or brain abnormalities

Rakotopare,

Lejour,

Duval

et al. 2023

Disease Models &Amp; Mechanisms

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p53 (encoded by Trp53) is a tumor suppressor, but mouse models have revealed that increased p53 activity may cause bone marrow failure, likely through dimerization partner, RB-like, E2F4/E2F5 and MuvB (DREAM) complex-mediated gene repression. Here, we designed a systematic approach to identify p53-DREAM pathway targets, the repression of which might contribute to abnormal hematopoiesis. We used Gene Ontology analysis to study transcriptomic changes associated with bone marrow cell differentiation, then chromatin immunoprecipitation-sequencing (ChIP-seq) data to identify DREAM-bound promoters. We next created positional frequency matrices to identify evolutionary conserved sequence elements potentially bound by DREAM. The same approach was developed to find p53-DREAM targets associated with brain abnormalities, also observed in mice with increased p53 activity. Putative DREAM-binding sites were found for 151 candidate target genes, of which 106 are mutated in a blood or brain genetic disorder. Twenty-one DREAM-binding sites were tested and found to impact gene expression in luciferase assays, to notably regulate genes mutated in dyskeratosis congenita (Rtel1), Fanconi anemia (Fanca), Diamond–Blackfan anemia (Tsr2), primary microcephaly [Casc5 (or Knl1), Ncaph and Wdr62] and pontocerebellar hypoplasia (Toe1). These results provide clues on the role of the p53-DREAM pathway in regulating hematopoiesis and brain development, with implications for tumorigenesis.

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Section: Discussionsupporting

confidence: 67%

A systematic approach identifies p53-DREAM pathway target genes associated with blood or brain abnormalities

Rakotopare,

Lejour,

Duval

et al. 2023

Disease Models &Amp; Mechanisms

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“…BRD8 binds acetylated histones through its bromodomain and is a component of the NuA4 chromatin-modifying complex 30, 41, 42 . Hence we expect reduced Brd8 expression will lead to changes in chromatin.…”

Section: Resultsmentioning

confidence: 99%

BRD8 guards the pluripotent state by sensing and maintaining histone acetylation

Sun,

Fu,

Xiao

et al. 2024

Preprint

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Epigenetic control of cell fates is a critical determinant to maintain cell type stability and permissive differentiation. However, the epigenetic control mechanisms are not well understood. Here, we show that the histone acetyltransferase reader protein BRD8 impairs the conversion of primed mouse EpiSCs (epiblast stem cells) to naive mouse ESCs (embryonic stem cells). BRD8 works by maintaining histone acetylation on promoters and transcribed gene bodies. BRD8 is responsible for maintaining open chromatin at somatic genes, and histone acetylation at naive-specific genes. When Brd8 expression was reduced, chromatin accessibility was unchanged, but histone acetylation at primed-specific genes was reduced. Conversely, naive-specific genes had reduced repressive chromatin marks, and acquired accessible chromatin more rapidly during the cell type conversion. We show that this process requires active histone deacetylation to promote the conversion of primed to naive. Our data supports a model for BRD8 reading histone acetylation to accurately localize the genome-wide binding of the histone acetyltransferase KAT5. Overall, this study shows how the reading of the histone acetylation state by BRD8 maintains cell type stability.

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“…It would be, for instance, of particular interest to evaluate the way it interferes with p53 and ATR/Chk1 signalling. On one hand, epigenetic reprogramming of p53 by bromodomain-containing protein 8 (BRD8) was most recently discovered as a key to glioblastoma aggressiveness [ 31 ]. On the other hand, the inhibition of ATR/Chk1-mediated DNA damage response inhibition is an attractive strategy against glioblastoma [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

Thymoquinone-protoflavone hybrid molecules as potential antitumor agents

Ahmed,

Tayeb,

Gonda

et al. 2024

PLoS ONE

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We describe herein the synthesis of eight new ester-coupled hybrid compounds from thymoquinone and protoflavone building blocks, and their bioactivity testing against multiple cancer cell lines. Among the hybrids, compound 14 showed promising activities in all cell lines studied. The highest activities were recorded against breast cancer cell lines with higher selectivity to MDA-MB-231 as compared to MCF-7. Even though the hybrids were found to be completely hydrolysed in 24 h under cell culture conditions, compound 14 demonstrated a ca. three times stronger activity against U-87 glioblastoma cells than a 1:1 mixture of its fragments. Further, compound 14 showed good tumour selectivity: it acted 4.4-times stronger on U-87 cells than on MRC-5 fibroblasts. This selectivity was much lower, only ca. 1.3-times, when the cells were co-treated with a 1:1 mixture of its non-coupled fragments. Protoflavone-thymoquinone hybrids may therefore serve as potential new antitumor leads particularly against glioblastoma.

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BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network

Cited by 32 publications

References 62 publications

A systematic approach identifies p53-DREAM pathway target genes associated with blood or brain abnormalities

A systematic approach identifies p53-DREAM pathway target genes associated with blood or brain abnormalities

BRD8 guards the pluripotent state by sensing and maintaining histone acetylation

Thymoquinone-protoflavone hybrid molecules as potential antitumor agents

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