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Glioblastoma With Wild-Type TP53 Linked to Potentially Targetable Epigenetic Alteration

NEW YORK – A team led by researchers at Cold Spring Harbor Laboratory has identified potentially treatable epigenetic changes in glioblastoma (GBM) with wild-type TP53 that have similar effects on cells compared to those found in TP53-mutated forms of the aggressive brain cancer.

The changes, not previously associated with GBM, are orchestrated by the BRD8 gene.

"Our findings demonstrated that BRD8 bypasses p53 tumor suppressive activity by enforcing a compact chromatin conformation to restrain the accessibility of p53 to its targets," senior and corresponding author Alea Mills, a researcher at Cold Spring Harbor Laboratory, and her colleagues wrote in Nature on Wednesday, adding that "GBM is sensitive to BRD8 depletion, which provides an encouraging way to awaken the sleeping guardian p53 in the majority of GBM cases."

Analyzing available tumor genome sequence data for more than 450 GBM cases, the researchers first identified features in GBM tumors with wild-type versions of the tumor suppressor gene p53 that were similar to p53-mutated GBM, prompting them to turn to CRISPR screening to search for possible epigenetic explanations.

After systematically targeting nearly 200 chromatin regulatory domains in TP53-wild type or TP53-mutated GBM cells and in more than two dozen other cancer cell lines, using 1,390 chromatin domain-targeting single-guide RNAs (sgRNAs), the team narrowed in on the bromodomain region of BRD8, a chromatin regulatory gene that mediates histone H2AZ residence at H2AZ binding sites.

In particular, the researchers noted that BRD8-targeting sgRNAs led to reduced survival of GBM cells containing wild-type TP53 — an effect not found with sgRNAs impacting intronic BRD8 sequences or in TP53-mutated GBM cells. Similarly, BRD8-targeting sgRNAs did not appear to have a significant impact on noncancerous, brain-derived neural stem cells, but did stretch out survival in mouse models with TP53-wild type GBM tumors.

With imaging, RNA sequencing, immunoprecipitation-mass spec, and other protein interaction analyses, the team then determined that enhanced BRD8 expression interferes with TP53's typical tumor suppressor role by interacting with the EP400 chromatin remodeling complex and H2AZ to block TP53 target sites.

"It's like BRD8 is saying 'NO ENTRY' to p53's tumor-preventing power, but when we hit BRD8 in the right way — go in there almost like a scalpel, but molecularly — the tumor is annihilated," CSHL's Mills said in a statement.

Because bromodomain inhibitors have shown promise in other cancer types, she and her coauthors speculated that it may one day be possible to remove the epigenetic block on p53 activity by directly targeting BRD8 in affected GBM cases.

"Notably, targeting the bromodomain of BRD8 displaces H2AZ, enhances chromatin accessibility, and engages p53 transactivation," the authors reported. "This in turn enforces cell cycle arrest and tumor suppression in [TP53-wild type] GBM."

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