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


ABSTRACT: 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. KrasG12D/+;Ezh2fl/fl mice exhibited shorter lifespan, more tumor lesions and higher tumor burden than KrasG12D/+ 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-?. 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.

SUBMITTER: Wang Y 

PROVIDER: S-EPMC5441181 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Wang Yanxiao Y   Hou Ning N   Cheng Xuan X   Zhang Jishuai J   Tan Xiaohong X   Zhang Chong C   Tang Yuling Y   Teng Yan Y   Yang Xiao X  

International journal of biological sciences 20170516 5


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 <i>EZH2</i> were also frequently present, with 14% of patients harboring loss-of-function <i>EZH2</i> alterations. To explore the effect of <i>Ezh2</i> loss on lung tumor formation, lung epithelial <i>Ezh2</i> gene  ...[more]

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