Inhibiting stromal Class I HDACs curbs pancreatic cancer progression

Gaoyang Liang, Tae Gyu Oh, Nasun Hah, Hervé Tiriac, Yu Shi, Morgan L. Truitt, Corina E. Antal, Annette R. Atkins, Yuwenbin Li, Cory Fraser, Serina Ng, Antonio F. M. Pinto, Dylan C. Nelson, Gabriela Estepa, Senada Bashi, Ester Banayo, Yang Dai, Christopher Liddle, Ruth T. Yu, Tony Hunter, Dannielle D. Engle, Haiyong Han, Daniel D. Von Hoff, Michael Downes () and Ronald M. Evans ()
Additional contact information
Gaoyang Liang: Salk Institute for Biological Studies
Tae Gyu Oh: Salk Institute for Biological Studies
Nasun Hah: Salk Institute for Biological Studies
Hervé Tiriac: University of California San Diego
Yu Shi: Salk Institute for Biological Studies
Morgan L. Truitt: Salk Institute for Biological Studies
Corina E. Antal: Salk Institute for Biological Studies
Annette R. Atkins: Salk Institute for Biological Studies
Yuwenbin Li: Salk Institute for Biological Studies
Cory Fraser: HonorHealth Scottsdale Osborn Medical Center and Shea Medical Center
Serina Ng: The Translational Genomic Research Institute
Antonio F. M. Pinto: Salk Institute for Biological Studies
Dylan C. Nelson: Salk Institute for Biological Studies
Gabriela Estepa: Salk Institute for Biological Studies
Senada Bashi: Salk Institute for Biological Studies
Ester Banayo: Salk Institute for Biological Studies
Yang Dai: Salk Institute for Biological Studies
Christopher Liddle: University of Sydney, Westmead Hospital
Ruth T. Yu: Salk Institute for Biological Studies
Tony Hunter: Salk Institute for Biological Studies
Dannielle D. Engle: Salk Institute for Biological Studies
Haiyong Han: The Translational Genomic Research Institute
Daniel D. Von Hoff: HonorHealth Scottsdale Osborn Medical Center and Shea Medical Center
Michael Downes: Salk Institute for Biological Studies
Ronald M. Evans: Salk Institute for Biological Studies

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42178-6

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