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BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma drives human dilated cardiomyopathy

ABSTRACT: By using a small molecule compound library targeting epigenetic enzymes we have identified BRD9 enzyme for eliminating CSCs. Genomic and proteomic studies revealed that BRD9/BAF complex regulates expression of stemness factors and chemoresistance by cooperating with TGFβ/Activin-SMAD2/3 signalling pathway. Chemical inhibition and genetic loss of function of BDR9 blocks the self-renewal of CSCs, reduces CSC invasiveness and resensitizes PDAC CSCs to conventional therapies. Analyses of chromatin architecture showed that BRD9 regulates the 3D chromatin looping between promoters and enhancers of stemness genes and EMT regulators in CSCs. BRD9 inhibition abrogated tumour formation in mice and eliminated CSCs in tumours from pancreatic cancer patients. Collectively, we uncovered BRD9 enzyme as an attractive therapeutic target for re-sensitizing and eliminating CSCs in pancreatic cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222952 | GEO | 2024/01/01

REPOSITORIES: GEO

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BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma drives human dilated cardiomyopathy

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BRD9-SMAD2/3 Orchestrates Stemness and Tumorigenesis in Pancreatic Ductal Adenocarcinoma.

Project description:Background & aimsThe dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood, which hampers the development of novel strategies for eliminating CSCs.MethodsBy small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodeling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signaling pathway.ResultsInhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumors from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs.ConclusionsCollectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

| S-EPMC11304550 | biostudies-literature

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