Cargando…
DZNep, an inhibitor of the histone methyltransferase EZH2, suppresses hepatic fibrosis through regulating miR-199a-5p/SOCS7 pathway
BACKGROUND: Hepatic fibrosis is a common response to chronic liver injury. Recently, the role of DZNep (a histone methyltransferase EZH2 inhibitor) in repressing pulmonary and renal fibrosis was verified. However, the potential effect of DZNep on hepatic fibrosis has not been elucidated. METHODS: Th...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
PeerJ Inc.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127960/ https://www.ncbi.nlm.nih.gov/pubmed/34040893 http://dx.doi.org/10.7717/peerj.11374 |
_version_ | 1783694033032314880 |
---|---|
author | Ding, Rongrong Zheng, Jianming Li, Ning Cheng, Qi Zhu, Mengqi Wang, Yanbing Zhou, Xinlan Zhang, Zhanqing Shi, Guangfeng |
author_facet | Ding, Rongrong Zheng, Jianming Li, Ning Cheng, Qi Zhu, Mengqi Wang, Yanbing Zhou, Xinlan Zhang, Zhanqing Shi, Guangfeng |
author_sort | Ding, Rongrong |
collection | PubMed |
description | BACKGROUND: Hepatic fibrosis is a common response to chronic liver injury. Recently, the role of DZNep (a histone methyltransferase EZH2 inhibitor) in repressing pulmonary and renal fibrosis was verified. However, the potential effect of DZNep on hepatic fibrosis has not been elucidated. METHODS: The hepatic fibrosis model was established in rats treated with CCl4 and in hepatic stellate cells (HSCs) treated with TGF-β1. The liver tissues were stained with H&E and Masson’s trichrome. The expression of EZH2, SOCS7, collagen I, αSMA mRNA and miR-199-5p was assessed using qPCR, immunohistochemical or western blot analysis. A dual-luciferase reporter assay was carried out to validate the regulatory relationship of miR-199a-5p with SOCS7. RESULTS: The EZH2 level was increased in CCl4-treated rats and in TGF-β1-treated HSCs, whereas DZNep treatment significantly inhibited EZH2 expression. DZNep repressed hepatic fibrosis in vivo and in vitro, as evidenced by the decrease of hepatic fibrosis markers (α-SMA and Collagen I). Moreover, miR-199a-5p expression was repressed by DZNep in TGF-β1-activated HSCs. Notably, downregulation of miR-199a-5p decreased TGF-β1-induced expression of fibrosis markers. SOCS7 was identified as a direct target of miR-199a-5p. The expression of SOCS7 was decreased in TGF-β1-activated HSCs, but DZNep treatment restore d SOCS7 expression. More importantly, SOCS7 knockdown decreased the effect of DZNep on collagen I and α SMA expression in TGF-β1-activated HSCs. CONCLUSIONS: DZNep suppresses hepatic fibrosis through regulating miR-199a-5p/SOCS7 axis, suggesting that DZNep may represent a novel treatment for fibrosis. |
format | Online Article Text |
id | pubmed-8127960 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | PeerJ Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-81279602021-05-25 DZNep, an inhibitor of the histone methyltransferase EZH2, suppresses hepatic fibrosis through regulating miR-199a-5p/SOCS7 pathway Ding, Rongrong Zheng, Jianming Li, Ning Cheng, Qi Zhu, Mengqi Wang, Yanbing Zhou, Xinlan Zhang, Zhanqing Shi, Guangfeng PeerJ Biochemistry BACKGROUND: Hepatic fibrosis is a common response to chronic liver injury. Recently, the role of DZNep (a histone methyltransferase EZH2 inhibitor) in repressing pulmonary and renal fibrosis was verified. However, the potential effect of DZNep on hepatic fibrosis has not been elucidated. METHODS: The hepatic fibrosis model was established in rats treated with CCl4 and in hepatic stellate cells (HSCs) treated with TGF-β1. The liver tissues were stained with H&E and Masson’s trichrome. The expression of EZH2, SOCS7, collagen I, αSMA mRNA and miR-199-5p was assessed using qPCR, immunohistochemical or western blot analysis. A dual-luciferase reporter assay was carried out to validate the regulatory relationship of miR-199a-5p with SOCS7. RESULTS: The EZH2 level was increased in CCl4-treated rats and in TGF-β1-treated HSCs, whereas DZNep treatment significantly inhibited EZH2 expression. DZNep repressed hepatic fibrosis in vivo and in vitro, as evidenced by the decrease of hepatic fibrosis markers (α-SMA and Collagen I). Moreover, miR-199a-5p expression was repressed by DZNep in TGF-β1-activated HSCs. Notably, downregulation of miR-199a-5p decreased TGF-β1-induced expression of fibrosis markers. SOCS7 was identified as a direct target of miR-199a-5p. The expression of SOCS7 was decreased in TGF-β1-activated HSCs, but DZNep treatment restore d SOCS7 expression. More importantly, SOCS7 knockdown decreased the effect of DZNep on collagen I and α SMA expression in TGF-β1-activated HSCs. CONCLUSIONS: DZNep suppresses hepatic fibrosis through regulating miR-199a-5p/SOCS7 axis, suggesting that DZNep may represent a novel treatment for fibrosis. PeerJ Inc. 2021-05-14 /pmc/articles/PMC8127960/ /pubmed/34040893 http://dx.doi.org/10.7717/peerj.11374 Text en ©2021 Ding et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited. |
spellingShingle | Biochemistry Ding, Rongrong Zheng, Jianming Li, Ning Cheng, Qi Zhu, Mengqi Wang, Yanbing Zhou, Xinlan Zhang, Zhanqing Shi, Guangfeng DZNep, an inhibitor of the histone methyltransferase EZH2, suppresses hepatic fibrosis through regulating miR-199a-5p/SOCS7 pathway |
title | DZNep, an inhibitor of the histone methyltransferase EZH2, suppresses hepatic fibrosis through regulating miR-199a-5p/SOCS7 pathway |
title_full | DZNep, an inhibitor of the histone methyltransferase EZH2, suppresses hepatic fibrosis through regulating miR-199a-5p/SOCS7 pathway |
title_fullStr | DZNep, an inhibitor of the histone methyltransferase EZH2, suppresses hepatic fibrosis through regulating miR-199a-5p/SOCS7 pathway |
title_full_unstemmed | DZNep, an inhibitor of the histone methyltransferase EZH2, suppresses hepatic fibrosis through regulating miR-199a-5p/SOCS7 pathway |
title_short | DZNep, an inhibitor of the histone methyltransferase EZH2, suppresses hepatic fibrosis through regulating miR-199a-5p/SOCS7 pathway |
title_sort | dznep, an inhibitor of the histone methyltransferase ezh2, suppresses hepatic fibrosis through regulating mir-199a-5p/socs7 pathway |
topic | Biochemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127960/ https://www.ncbi.nlm.nih.gov/pubmed/34040893 http://dx.doi.org/10.7717/peerj.11374 |
work_keys_str_mv | AT dingrongrong dznepaninhibitorofthehistonemethyltransferaseezh2suppresseshepaticfibrosisthroughregulatingmir199a5psocs7pathway AT zhengjianming dznepaninhibitorofthehistonemethyltransferaseezh2suppresseshepaticfibrosisthroughregulatingmir199a5psocs7pathway AT lining dznepaninhibitorofthehistonemethyltransferaseezh2suppresseshepaticfibrosisthroughregulatingmir199a5psocs7pathway AT chengqi dznepaninhibitorofthehistonemethyltransferaseezh2suppresseshepaticfibrosisthroughregulatingmir199a5psocs7pathway AT zhumengqi dznepaninhibitorofthehistonemethyltransferaseezh2suppresseshepaticfibrosisthroughregulatingmir199a5psocs7pathway AT wangyanbing dznepaninhibitorofthehistonemethyltransferaseezh2suppresseshepaticfibrosisthroughregulatingmir199a5psocs7pathway AT zhouxinlan dznepaninhibitorofthehistonemethyltransferaseezh2suppresseshepaticfibrosisthroughregulatingmir199a5psocs7pathway AT zhangzhanqing dznepaninhibitorofthehistonemethyltransferaseezh2suppresseshepaticfibrosisthroughregulatingmir199a5psocs7pathway AT shiguangfeng dznepaninhibitorofthehistonemethyltransferaseezh2suppresseshepaticfibrosisthroughregulatingmir199a5psocs7pathway |