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

Cancer Stem Cells Cancer Therapy Epigenetics Pancreatic Cancer TGFβ/Activin-SMAD2/3

Journal

Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630

Informations de publication

Date de publication:
21 Sep 2023
Historique:
received: 28 02 2023
revised: 06 09 2023
accepted: 11 09 2023
pubmed: 23 9 2023
medline: 23 9 2023
entrez: 22 9 2023
Statut: aheadofprint

Résumé

The 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. By 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. Inhibition 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. Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

Sections du résumé

BACKGROUND & AIMS OBJECTIVE
The 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.
METHODS METHODS
By 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.
RESULTS RESULTS
Inhibition 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.
CONCLUSIONS CONCLUSIONS
Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

Identifiants

DOI: 10.1053/j.gastro.2023.09.021 PMID: 37739089
pubmed: 37739089
pii: S0016-5085(23)05012-6
doi: 10.1053/j.gastro.2023.09.021
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Commentaires et corrections

Type : UpdateOf

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Auteurs

Yuliang Feng (Y)

Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.

Liuyang Cai (L)

Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Guangdong, China.

Martin Pook (M)

Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.

Feng Liu (F)

Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.

Chao-Hui Chang (CH)

Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.

Mai Abdel Mouti (MA)

Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.

Reshma Nibhani (R)

Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.

Stefania Militi (S)

Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.

James Dunford (J)

Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.

Martin Philpott (M)

Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.

Yanbo Fan (Y)

Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Guo-Chang Fan (GC)

Departments of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Qi Liu (Q)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Jun Qi (J)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Cheng Wang (C)

Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.

Wanzi Hong (W)

Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, China.

Hannah Morgan (H)

Heart, Lung and Vascular Institute, Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, Ohio.

Mingyang Wang (M)

College of Engineering and Applied Science, University of Cincinnati, Cincinnati, Ohio.

Sakthivel Sadayappan (S)

Heart, Lung and Vascular Institute, Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, Ohio.

Anil G Jegga (AG)

Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Computer Science, University of Cincinnati College of Engineering, Cincinnati, Ohio.

Udo Oppermann (U)

Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom; Oxford Translational Myeloma Centre, Botnar Research Centre, Oxford, United Kingdom.

Yigang Wang (Y)

Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: wanyy@ucmail.uc.edu.

Wei Huang (W)

Heart, Lung and Vascular Institute, Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, Ohio. Electronic address: huangwe@ucmail.uc.edu.

Lei Jiang (L)

Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, China. Electronic address: jianglei0731@gmail.com.

Siim Pauklin (S)

Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom. Electronic address: siim.pauklin@ndorms.ox.ac.uk.

Classifications MeSH