期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 13, 期 5, 页码 652-659出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.19108
关键词
Ezh2; tumor suppressor; Kras; lung adenocarcinoma
资金
- National Natural Science Foundation of China [81572717, 31430057, 31630093, 81272702, 31571512]
- Chinese National Key Program on Basic Research [2012CB945103]
- National Key Research and Development Program of China [2016YFC1300600]
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-alpha. 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据