Ezh2 Acts as a Tumor Suppressor in Kras-driven Lung Adenocarcinoma

Previous studies have suggested that enhancer zeste homolog 2 (EZH2), a Histone Methyltransferase subunit of polycomb repressive complex 2 (PRC2), acts as an oncogene in Lung Adenocarcinoma (ADC) development. However, we found that in human lung ADC samples, deletion and mutations of EZH2 were also frequently present, with 14% of patients harboring loss-of-function EZH2 alterations. To explore the effect of EZH2 loss on lung tumor formation, lung epithelial EZH2 gene was deleted in Kras-driven lung ADC mouse model. Unexpectedly, EZH2 loss dramatically promoted Kras-driven ADC formation. Kras^G12D/+;Ezh2^fl/fl mice exhibited shorter lifespan, more tumor lesions and higher tumor burden than Kras^G12D/+ mice, suggesting the tumor-suppressive role of EZH2 in Kras-driven ADCs. Mechanistically, EZH2 loss amplified Akt and ERK activation through de-repressing its target insulin-like growth factor 1 (Igf1). Additionally, EZH2 loss cooperated with Kras mutation to exacerbate the inflammatory response, as shown by massive macrophage and neutrophil infiltrates, as well as a marked increase in tumor-associated cytokines such as IL-6 and TNF-α. Taken together, our findings revealed the tumor suppressive function of EZH2 in Kras-driven ADCs, underlining the importance of revaluating the application of EZH2 inhibitors in a variety of cancers.