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Inhibiting stromal Class I HDACs curbs pancreatic cancer progression.

  • 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
  • And 5 more
Publication Date
Dec 06, 2023
eScholarship - University of California
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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.

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