EZH2 promotes the expression of LPA1 by mediating microRNA-139 promoter methylation to accelerate the development of ova
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Cancer Cell International Open Access
PRIMARY RESEARCH
EZH2 promotes the expression of LPA1 by mediating microRNA‑139 promoter methylation to accelerate the development of ovarian cancer Dongbo Wu1, Fanglan Wu2, Birong Li3, Wei Huang3* and Donglian Wang4
Abstract Background: It has been known that ovarian cancer (OC) is a leading cause for women mortality globally. We aimed to analyze the underlying mechanism supporting that enhancer of zeste homolog 2 (EZH2) affected the development of OC via the involvement of microRNA-139 (miR-139)/transforming growth factor beta (TGF-β)/lysophosphatidic acid-1 (LPA1) axis. Methods: High expression patterns of EZH2 and miR-139 and low LPA1 expression pattern in OC were evaluated using RT-qPCR and immunoblotting, while their correlation was assessed by the Spearman’s rank and Pearson’s correlation coefficient. Subsequently, dual-luciferase reporter gene assay was applied to validate the binding relationship between miR-139 and LPA1, while H3K27me enrichment was assessed by ChIP assay. After that, the effects of altered expression of EZH2, miR-194, or LPA1 on the cell biological functions and the expression pattern of TGF-related factors were evaluated. Results: We found that EZH2 repressed the miR-139 expression pattern by recruiting H3K27me3 to promote miR-139 promoter methylation, while silencing of EZH2 suppressed in vitro cancer progression by increasing miR-139. LPA1 was a target of miR-139, and could activate the TGF-β signaling pathway, which hastened the OC progression. miR139-targeted inhibition of LPA1 and LPA1-activated TGF-β signaling pathway were evidenced to be critical mechanisms underlying the effects of EZH2 on OC cells. Lastly, silencing of EZH2 inhibited the xenograft growth in vivo. Conclusions: EZH2 could down-regulate miR-139 expression pattern by recruiting H3K27me3 to promote the miR139 promoter methylation and activate the TGF-β pathway by up-regulating LPA1, which contributed to the progression of OC. The current study may possess potentials for OC treatment. Keywords: Ovarian cancer, Tumor growth, Enhancer of zeste 2 polycomb repressive complex 2 subunit, microRNA-139
*Correspondence: [email protected] 3 Department of Gynecology, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), No. 61, Western Jiefang Road, Changsha 410000, Hunan, People’s Republic of China Full list of author information is available at the end of the article
Background Ovarian cancer (OC), a prevalent type of cancer affecting women, was causative of 184,799 deaths globally in 2018 [1]. On the basis of OC pathogenesis and prognosis, the disease can be categorized into five subtypes: highgrade serous, clear-cell, endometrioid, and mucinous, as well as low-grade serous cancer [2]. Due to the intricate etiology of OC influenced by numerous factors, various
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