학술논문
Inhibiting stromal Class I HDACs curbs pancreatic cancer progression.
Document Type
article
Author
Liang, Gaoyang; Oh, Tae; Hah, Nasun; Tiriac, Hervé; Shi, Yu; Truitt, Morgan; Antal, Corina; Atkins, Annette; Li, Yuwenbin; Fraser, Cory; Ng, Serina; Pinto, Antonio; Nelson, Dylan; Estepa, Gabriela; Bashi, Senada; Banayo, Ester; Dai, Yang; Liddle, Christopher; Yu, Ruth; Hunter, Tony; Engle, Dannielle; Han, Haiyong; Von Hoff, Daniel; Downes, Michael; Evans, Ronald
Source
Nature Communications. 14(1)
Subject
Language
Abstract
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.