HDAC2 Facilitates Pancreatic Cancer Metastasis

Lukas Krauß, Bettina C. Urban, Sieglinde Hastreiter, Carolin Schneider, Patrick Wenzel, Zonera Hassan, Matthias Wirth, Katharina Lankes, Andrea Terrasi, Christine Klement, Filippo M. Cernilogar, Rupert Ollinger, Niklas De Andrade Krätzig, Thomas Engleitner, Roland M. Schmid, Katja Steiger, Roland Rad, Oliver H. Krämer, Maximilian Reichert, Gunnar SchottaDieter Saur, Gunter Schneider

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The mortality of patients with pancreatic ductal adenocarcinoma (PDAC) is strongly associated with metastasis, a multistep 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 prosurvival receptor tyrosine kinases connected to mesenchymal PDAC, including PDGFRa, PDGFRβ, and EGFR. The HDAC2-maintained program disabled the tumor-suppressive arm of the TGFβ pathway, explaining impaired metastasis formation of HDAC2-deficient PDAC. These data identify 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. Significance: HDAC2 has a context-specific role in undifferentiated PDAC and the capacity to disseminate systemically, implicating HDAC2 as targetable protein to prevent metastasis.

Original languageEnglish
Pages (from-to)695-707
Number of pages13
JournalCancer Research
Volume82
Issue number4
DOIs
StatePublished - 15 Feb 2022

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