Epigenetic Targets of EZH2 in Lung Adenocarcinoma

EZH2 is a histone methyltransferase that silences distinct sets of genes embryonic stem cells, adult stem cells and cancer. In cancer, EZH2 may act to promote growth and self-renewal, or cell cycle arrest and differentiation in different cellular contexts. Since EZH2 inhibitors have been developed and are currently in clinical trials for many cancer types, understanding the role of EZH2 in lung tumor initiation and progression is an important pursuit. To this end, we bred the Ezh2 conditional (floxed) mice to the genetic mouse model of lung adenocarcinoma: the LSL:KrasG12D; p53 floxed (Kras/p53) mouse. Intranasal adeno-Cre virus was administered to activate oncogenic Kras, delete p53 and delete one or two copies of Ezh2. We expected that Ezh2 deletion would lower tumor burden, due to many studies, including our own, implicating EZH2 as an oncogene in lung cancer. Indeed, we found that when compared to Kras/p53 mice WT for EZH2, Ezh2 heterozygous mice had lower tumor burden. However, mice with two floxed alleles of Ezh2 had higher tumor burden and higher tumor grade than either WT or heterozygous mice. This unexpected result implicates the dosage of EZH2 as critical to the oncogenic process.