The mortality of patients with pancreatic ductal adenocarcinoma (PDAC) is strongly associated with metastasis, a multi-step process that is incompletely understood in this disease. Although genetic drivers of PDAC metastasis have not been defined, transcriptional and epigenetic rewiring can contribute to the metastatic process. The epigenetic eraser histone deacetylase 2 (HDAC2) has been connected to less differentiated PDAC, but the function of HDAC2 in PDAC has not been comprehensively evaluated. Using genetically defined models, we show that HDAC2 is a cellular fitness factor that controls cell cycle in vitro and metastasis in vivo, particularly in undifferentiated, mesenchymal PDAC cells.Unbiased expression profiling detected a core set of HDAC2-regulated genes. HDAC2 controlled expression of several pro-survival receptor tyrosine kinases connected to mesenchymal PDAC, including PDGFRα, PDGFRβ, and EGFR. The HDAC2-maintained program disabled the tumor-suppressive arm of the TGFβ-pathway, explaining impaired metastasis formation of HDAC2-deficient PDAC. This data identifies HDAC2 as a tractable player in the PDAC metastatic cascade. The complexity of the function of epigenetic regulators like HDAC2 implicates that an increased understanding of these proteins is needed for implementation of effective epigenetic therapies.
SignificanceHDAC2 has a context-specific role in undifferentiated PDAC and its capacity to disseminate systemically, implicating HDAC2 as targetable protein to prevent metastasis.Research.
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