EZH2 regulates pancreatic cancer subtype identity and tumor progression via transcriptional repression of gata6

Shilpa Patil, Benjamin Steuber, Waltraut Kopp, Vijayalakshmi Kari, Laura Urbach, Xin Wang, Stefan Kuffer, Hanibal Bohnenberger, Dimitra Spyropoulou, Zhe Zhang, Lennart Versemann, Mark Sebastian Bosherz, Marius Brunner, Jochen Gaedcke, Philipp Strobel, Jin San Zhang, Albrecht Neesse, Volker Ellenrieder, Shiv K. Singh, Steven A. JohnsenElisabeth Hessmann

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Recent studies have thoroughly described genome-wide expression patterns defining molecular subtypes of pancreatic ductal adenocarcinoma (PDAC), with different prognostic and predictive implications. Although the reversible nature of key regulatory transcription circuits defining the two extreme PDAC subtype lineages “classical” and “basal-like” suggests that subtype states are not permanently encoded but underlie a certain degree of plasticity, pharmacologically actionable drivers of PDAC subtype identity remain elusive. Here, we characterized the mechanistic and functional implications of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in controlling PDAC plasticity, dedifferentiation, and molecular subtype identity. Utilization of transgenic PDAC models and human PDAC samples linked EZH2 activity to PDAC dedifferentiation and tumor progression. Combined RNA- and chromatin immunoprecipitation sequencing studies identified EZH2 as a pivotal suppressor of differentiation programs in PDAC and revealed EZH2-dependent transcriptional repression of the classical subtype defining transcription factor Gata6 as a mechanistic basis for EZH2-dependent PDAC progression. Importantly, genetic or pharmacologic depletion of EZH2 sufficiently increased GATA6 expression, thus inducing a gene signature shift in favor of a less aggressive and more therapy-susceptible, classical PDAC subtype state. Consistently, abrogation of GATA6 expression in EZH2-deficient PDAC cells counteracted the acquisition of classical gene signatures and rescued their invasive capacities, suggesting that GATA6 derepression is critical to overcome PDAC progression in the context of EZH2 inhibition. Together, our findings link the EZH2-GATA6 axis to PDAC subtype identity and uncover EZH2 inhibition as an appealing strategy to induce subtype-switching in favor of a less aggressive PDAC phenotype.

Original languageEnglish (US)
Pages (from-to)4620-4632
Number of pages13
JournalCancer research
Issue number21
StatePublished - Nov 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'EZH2 regulates pancreatic cancer subtype identity and tumor progression via transcriptional repression of gata6'. Together they form a unique fingerprint.

Cite this