BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma
<p><strong>Background and Aims</strong></p> 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 ar...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Journal article |
| Idioma: | English |
| Publicado: |
Elsevier
2023
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| _version_ | 1826312598304325632 |
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| author | Feng, Y Cai, L Pook, M Liu, F Chang, C-H Mouti, MA Nibhani, R Militi, S Dunford, J Philpott, M Fan, Y Fan, G-C Liu, Q Qi, J Wang, C Hong, W Morgan, H Wang, M Sadayappan, S Jegga, AG Oppermann, U Wang, Y Huang, W Jiang, L Pauklin, S |
| author_facet | Feng, Y Cai, L Pook, M Liu, F Chang, C-H Mouti, MA Nibhani, R Militi, S Dunford, J Philpott, M Fan, Y Fan, G-C Liu, Q Qi, J Wang, C Hong, W Morgan, H Wang, M Sadayappan, S Jegga, AG Oppermann, U Wang, Y Huang, W Jiang, L Pauklin, S |
| author_sort | Feng, Y |
| collection | OXFORD |
| description | <p><strong>Background and Aims</strong></p>
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.
<p><strong>Methods</strong></p>
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.
<p><strong>Results</strong></p>
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.
<p><strong>Conclusions</strong></p>
Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness. |
| first_indexed | 2024-03-07T08:08:44Z |
| format | Journal article |
| id | oxford-uuid:d6d9d357-aec1-4d8a-8a7c-72e03243ef30 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-04-09T03:56:23Z |
| publishDate | 2023 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:d6d9d357-aec1-4d8a-8a7c-72e03243ef302024-03-18T09:17:00ZBRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinomaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d6d9d357-aec1-4d8a-8a7c-72e03243ef30EnglishSymplectic ElementsElsevier2023Feng, YCai, LPook, MLiu, FChang, C-HMouti, MANibhani, RMiliti, SDunford, JPhilpott, MFan, YFan, G-CLiu, QQi, JWang, CHong, WMorgan, HWang, MSadayappan, SJegga, AGOppermann, UWang, YHuang, WJiang, LPauklin, S<p><strong>Background and Aims</strong></p> 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. <p><strong>Methods</strong></p> 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. <p><strong>Results</strong></p> 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. <p><strong>Conclusions</strong></p> Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness. |
| spellingShingle | Feng, Y Cai, L Pook, M Liu, F Chang, C-H Mouti, MA Nibhani, R Militi, S Dunford, J Philpott, M Fan, Y Fan, G-C Liu, Q Qi, J Wang, C Hong, W Morgan, H Wang, M Sadayappan, S Jegga, AG Oppermann, U Wang, Y Huang, W Jiang, L Pauklin, S BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma |
| title | BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma |
| title_full | BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma |
| title_fullStr | BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma |
| title_full_unstemmed | BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma |
| title_short | BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma |
| title_sort | brd9 smad2 3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma |
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