Author:
Feng Yuliang,Cai Liuyang,Pook Martin,Liu Feng,Chang Chao-Hui,Mouti Mai Abdel,Nibhani Reshma,Wu Shihong,Deng Siwei,Militi Stefania,Dunford James,Philpott Martin,Fan Yanbo,Fan Guo-Chang,Liu Qi,Qi Jun,Sadayappan Sakthivel,Jegga Anil G.,Oppermann Udo,Wang Yigang,Huang Wei,Jiang Lei,Pauklin Siim
Abstract
AbstractThe 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. By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodelling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signalling pathway. Inhibition and genetic ablation of BDR9 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 tumours 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.
Publisher
Cold Spring Harbor Laboratory