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Inhibiting stromal Class I HDACs curbs pancreatic cancer progression
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Journal Article
Inhibiting stromal Class I HDACs curbs pancreatic cancer progression
2023
Overview
Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.
The desmoplastic stroma constitutes part of the microenvironment in pancreatic ductal adenocarcinoma. Here the authors show that Class I HDACs regulate the pro-desmoplastic and pro-tumorigenic transcriptional programs to support stromal activation and tumour progression.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 38/90
/ 38/91
/ 45/41
/ 64/60
/ 96/1
/ 96/106
/ 96/109
/ 96/21
/ 96/31
/ Animals
/ Cancer
/ Carcinoma, Pancreatic Ductal - drug therapy
/ Carcinoma, Pancreatic Ductal - genetics
/ Carcinoma, Pancreatic Ductal - metabolism
/ Histones
/ Humanities and Social Sciences
/ Leukemia
/ Mice
/ Pancreatic Neoplasms - drug therapy
/ Pancreatic Neoplasms - genetics
/ Pancreatic Neoplasms - metabolism
/ Science
/ Stroma
/ Tumors
