EZH2 and Endometrial Cancer Development: Insights from a Mouse Model

Authors

Xin Fang
Nan Ni
Xiaofang Wang
Yanan Tian
Ivan Ivanov
Monique Rijnkels
Kayla J Bayless
John P Lydon
Qinglei Li

Publication Date

3-7-2022

Journal

Cells

DOI

10.3390/cells11050909

PMID

35269532

PMCID

PMC8909840

PubMedCentral® Posted Date

3-7-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Carcinogenesis, Disease Models, Animal, Endometrial Neoplasms, Enhancer of Zeste Homolog 2 Protein, Female, Humans, Mice, Polycomb Repressive Complex 2, Uterus, Ezh2, endometrial cancer, Pten, mouse model

Abstract

Enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive complex 2, plays an important role in cancer development. As both oncogenic and tumor suppressive functions of EZH2 have been documented in the literature, the objective of this study is to determine the impact of Ezh2 deletion on the development and progression of endometrial cancer induced by inactivation of phosphatase and tensin homolog (PTEN), a tumor suppressor gene frequently dysregulated in endometrial cancer patients. To this end, we created mice harboring uterine deletion of both Ezh2 and Pten using Cre recombinase driven by the progesterone receptor (Pgr) promoter. Our results showed reduced tumor burden in Pten^d/d; Ezh2^d/d mice compared with that of Pten^d/d mice during early carcinogenesis. The decreased Ki67 index in EZH2 and PTEN-depleted uteri versus that in PTEN-depleted uteri indicated an oncogenic role of EZH2 during early tumor development. However, mice harboring uterine deletion of both Ezh2 and Pten developed unfavorable disease outcome, accompanied by exacerbated epithelial stratification and heightened inflammatory response. The observed effect was non-cell autonomous and mediated by altered immune response evidenced by massive accumulation of intraluminal neutrophils, a hallmark of endometrial carcinoma in Pten^d/d; Ezh2^d/d mice during disease progression. Hence, these results reveal dual roles of EZH2 in endometrial cancer development.