EZH2, an epigenetic factor involved in oncogenic properties of ATM deficient PDAC subtypes?

Despite decades of extensive basic and translational research improving our understanding of pancreatic ductal adenocarcinoma (PDAC) biology, PDAC is predicted to become the second-leading cause of cancer-related death in 2030. Due to its resistance towards conventional therapies and its heterogeneous mutational landscape, the molecular stratification and the development of targeted therapeutic options is essential for improving survival in PDAC patients. PDAC harbours recurrent functional mutations of the DNA damage response serine/threonine kinase ATM (ataxia telangiectasia mutated), which has been shown to accelerate tumorigenesis as well as tumour cell plasticity. We previously found that loss of ATM coincides with oncogenic programs including epithelial-mesenchymal transition (EMT) and stemness behaviour. Preliminary data show an overexpression of the histone-methyltransferase EZH2 (enhancer of zeste homolog 2) in our AKC (Ptf1a^Cre/+; Atm^fl/fl; LSL-Kras^G12D/+ ) transgenic mouse model, which leads us to question the role of this epigenetic factor in ATM-deficient PDAC subtypes.

In order to decipher oncogenic EZH2-functions during pancreatic tumorigenesis, a transgenic mouse model displaying both ATM and EZH2 depletion in a Kras^G12D activated context was generated (AKEC mice). Initial data from the characterization of our model suggest that AKEC mice experience longer survival and a reduced tumour incidence compared to AKC animals. Interestingly, in vitro analyses conducted with isolated pancreatic tumour cells reveal that EZH2-loss is associated with the regulation of several EMT genes, suggesting a favourable role of this epigenetic factor in invasive properties of ATM-deficient PDAC cells. Furthermore, we observe that loss of ATM is associated with modifications of the post-translational regulation of the protein EZH2, which could explain its overexpression and its damaging activity during pancreatic tumorigenesis.

Altogether, our results suggest that ATM-deficiency significantly impacts EZH2-dependant gene regulation and functions, hence molecular stratification of ATM status prior to pharmacologically interfering with EZH2 inhibitors in PDAC therapies is considered essential.

Publication History

Article published online:
08 September 2020