EZH2 promotes the expression of LPA1 by mediating microRNA-139 promoter methylation to accelerate the development of ovarian cancer
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 gr...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-11-01
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| Series: | Cancer Cell International |
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| Online Access: | http://link.springer.com/article/10.1186/s12935-020-01622-z |
| _version_ | 1829116705200144384 |
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| author | Dongbo Wu Fanglan Wu Birong Li Wei Huang Donglian Wang |
| author_facet | Dongbo Wu Fanglan Wu Birong Li Wei Huang Donglian Wang |
| author_sort | Dongbo Wu |
| collection | DOAJ |
| description | 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. miR-139-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 miR-139 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. |
| first_indexed | 2024-12-12T16:38:03Z |
| format | Article |
| id | doaj.art-da1ec5de33474459a61014414d50088c |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-12-12T16:38:03Z |
| publishDate | 2020-11-01 |
| publisher | BMC |
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| series | Cancer Cell International |
| spelling | doaj.art-da1ec5de33474459a61014414d50088c2022-12-22T00:18:37ZengBMCCancer Cell International1475-28672020-11-0120111610.1186/s12935-020-01622-zEZH2 promotes the expression of LPA1 by mediating microRNA-139 promoter methylation to accelerate the development of ovarian cancerDongbo Wu0Fanglan Wu1Birong Li2Wei Huang3Donglian Wang4Department of Obstetrics and Gynecology, The First Hospital of ChangshaDepartment of Clinical Laboratory, The First Hospital of ChangshaDepartment of Gynecology, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Department of Gynecology, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Department of Gynecology, The Maternal and Child Health Hospital of Hunan ProvinceAbstract 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. miR-139-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 miR-139 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.http://link.springer.com/article/10.1186/s12935-020-01622-zOvarian cancerTumor growthEnhancer of zeste 2 polycomb repressive complex 2 subunitmicroRNA-139 |
| spellingShingle | Dongbo Wu Fanglan Wu Birong Li Wei Huang Donglian Wang EZH2 promotes the expression of LPA1 by mediating microRNA-139 promoter methylation to accelerate the development of ovarian cancer Cancer Cell International Ovarian cancer Tumor growth Enhancer of zeste 2 polycomb repressive complex 2 subunit microRNA-139 |
| title | EZH2 promotes the expression of LPA1 by mediating microRNA-139 promoter methylation to accelerate the development of ovarian cancer |
| title_full | EZH2 promotes the expression of LPA1 by mediating microRNA-139 promoter methylation to accelerate the development of ovarian cancer |
| title_fullStr | EZH2 promotes the expression of LPA1 by mediating microRNA-139 promoter methylation to accelerate the development of ovarian cancer |
| title_full_unstemmed | EZH2 promotes the expression of LPA1 by mediating microRNA-139 promoter methylation to accelerate the development of ovarian cancer |
| title_short | EZH2 promotes the expression of LPA1 by mediating microRNA-139 promoter methylation to accelerate the development of ovarian cancer |
| title_sort | ezh2 promotes the expression of lpa1 by mediating microrna 139 promoter methylation to accelerate the development of ovarian cancer |
| topic | Ovarian cancer Tumor growth Enhancer of zeste 2 polycomb repressive complex 2 subunit microRNA-139 |
| url | http://link.springer.com/article/10.1186/s12935-020-01622-z |
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