Abstract
Enhancer of zeste homolog 2 (EZH2), a catalytic core component of the Polycomb repressive complex 2 (PRC2), stimulates the silencing of target genes through histone H3 lysine 27 trimethylation (H3K27me3). Recent findings have indicated EZH2 is involved in the development and progression of various human cancers. However, the exact mechanism of EZH2 in the promotion of cervical cancer is largely unknown. Here, we show that EZH2 expression gradually increases during the progression of cervical cancer. We identified a significant positive correlation between EZH2 expression and cell proliferation in vitro and tumor formation in vivo by the up-regulation or down-regulation of EZH2 using CRISPR-Cas9-mediated gene editing technology and shRNA in HeLa and SiHa cells. Further investigation indicated that EZH2 protein significantly accelerated the cell cycle transition from the G0/G1 to S phase. TOP/FOP-Flash reporter assay revealed that EZH2 significantly activated Wnt/β-catenin signaling and the target genes of Wnt/β-catenin pathway were up-regulated, including β-catenin, cyclin D1, and c-myc. Moreover, dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays confirmed that EZH2 inhibited the expression of glycogen synthase kinase-3β (GSK-3β) and TP53 through physically interacting with motifs in the promoters of the GSK-3β and TP53 genes. Additionally, blockage of the Wnt/β-catenin pathway resulted in significant inhibition of cell proliferation, and activation of the Wnt/β-catenin pathway resulted in significant enhancement of cell proliferation, as induced by EZH2. Taken together, our data demonstrate that EZH2 promotes cell proliferation and tumor formation in cervical cancer through activating the Wnt/β-catenin pathway by epigenetic silencing via GSK-3β and TP53.
Highlights
Cervical cancer is the fourth most common tumor type and the fourth leading cause of cancer death among women worldwide, and its incidence has increased in recent years [1]
Analysis of the IHC scores revealed that the immunoreactivity score (IRS) of Enhancer of zeste homolog 2 (EZH2) staining was 1.5 for the normal cervical tissues, 3.1 for the carcinoma in situ (CIS) tissues and 6.6 for the cervical cancer tissues (p
The cervical cancer tissues had a 17-fold higher EZH2 expression level than the normal cervical tissues (Figure 1E, p
Summary
Cervical cancer is the fourth most common tumor type and the fourth leading cause of cancer death among women worldwide, and its incidence has increased in recent years [1]. 90% of cervical cancer deaths have occurred in developing regions of the world. To develop better prognostic and therapeutic strategies for cervical cancer, in-depth research into the molecular and biologic mechanisms of oncogenesis is critical. It is known that the development of cervical cancer is intimately associated with high-risk human papillomavirus (HPV) infection, progression of a HPVpositive premalignant lesion to invasive carcinoma is a rare event [2]. Not all patients infected with HPV develop cervical cancer and various molecular abnormalities, including the inactivation of tumor suppressor genes and activation of oncogenes, which are essential for cervical cancer development [3]. Extensive studies have shown that both genetic changes and epigenetic modifications may play important roles in complex signaling pathways in carcinogenesis [4,5,6], but the underlying mechanism of cervical cancer has not yet been clearly elucidated
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