Dataset Information

YAP1/Twist promotes fibroblast activation and lung fibrosis that conferred by miR-15a loss in IPF.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic parenchymal lung disease of unknown etiology and lack effective interventions. Using a combination of in vitro and in vivo studies, we found that overexpression of YAP1, a key effector in the Hippo pathway, promoted cell proliferation, migration, and collagen production in lung fibroblasts. Furthermore, the pro-fibrotic action of YAP1 was mediated by transcriptional activation of Twist1 through interacting with its partner TEAD. In contrast, knockdown of YAP1 inhibited extracellular matrix (ECM) deposition, which ultimately ameliorated lung fibrosis in vitro and in vivo. Additionally, we constructed a dysregulated miRNA regulatory network that affects the expression of the Hippo pathway effectors in IPF and identified miR-15a, which is significantly down-regulated in IPF patients, as one of the most essential miRNAs regulating this pathway. Moreover, knockdown of miR-15a resulted in fibroblast activation and lung fibrosis through promoting Twist expression by targeting inhibition of YAP1. In contrast, therapeutic restoration of miR-15a inhibits fibrogenesis in lung fibroblast and abrogated BLM-induced lung fibrosis in mice. These results highlight a role for miR-15a/YAP1/Twist axis in IPF that offer novel strategies for the prevention and treatment of lung fibrosis.

SUBMITTER: Chen Y

PROVIDER: S-EPMC6748107 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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YAP1/Twist promotes fibroblast activation and lung fibrosis that conferred by miR-15a loss in IPF.

Chen Yingzhun Y Zhao Xiaoguang X Sun Jian J Su Wei W Zhang Lu L Li Yingnan Y Liu Yingqi Y Zhang Lijia L Lu Yanjie Y Shan Hongli H Liang Haihai H

Cell death and differentiation 20190115 9

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic parenchymal lung disease of unknown etiology and lack effective interventions. Using a combination of in vitro and in vivo studies, we found that overexpression of YAP1, a key effector in the Hippo pathway, promoted cell proliferation, migration, and collagen production in lung fibroblasts. Furthermore, the pro-fibrotic action of YAP1 was mediated by transcriptional activation of Twist1 through interacting with its partner T ...[more]

PMID: 30644438

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Project description:BackgroundN6-methyladenosine (m6A) is the most common and abundant internal modification of RNA. Its critical functions in multiple physiological and pathological processes have been reported. However, the role of m6A in silica-induced pulmonary fibrosis has not been fully elucidated. AlkB homolog 5 (ALKBH5), a well-known m6A demethylase, is upregulated in the silica-induced mouse pulmonary fibrosis model. Here, we sought to investigate the function of ALKBH5 in pulmonary fibrosis triggered by silica inhalation.MethodsWe performed studies with fibroblast cell lines and silica-induced mouse pulmonary fibrosis models. The expression of ALKBH5, miR-320a-3p, and forkhead box protein M1 (FOXM1) was determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. RNA immunoprecipitation (RIP) assays and m6A RNA immunoprecipitation assays (MeRIP), western bolt, immunofluorescence assays, and 5-ethynyl-2'-deoxyuridine (EdU) fluorescence staining were performed to explore the roles of ALKBH5, miR-320a-3p, and FOXM1 in fibroblast activation.ResultsALKBH5 expression was increased in silica-inhaled mouse lung tissues and transforming growth factor (TGF)-β1-stimulated fibroblasts. Moreover, ALKBH5 knockdown exerted antifibrotic effects in vitro. Simultaneously, downregulation of ALKBH5 elevated miR-320a-3p but decreased pri-miR-320a-3p. Mechanically, ALKBH5 demethylated pri-miR-320a-3p, thus blocking the microprocessor protein DGCR8 from interacting with pri-miR-320a-3p and leading to mature process blockage of pri-miR-320a-3p. We further demonstrated that miR-320a-3p could regulate fibrosis by targeting FOXM1 messenger RNA (mRNA) 3'-untranslated region (UTR). Notably, our study also verified that ALKBH5 could also directly regulate FOXM1 in an m6A-dependent manner.ConclusionsOur findings suggest that ALKBH5 promotes silica-induced lung fibrosis via the miR-320a-3p/FOXM1 axis or targeting FOXM1 directly. Approaches aimed at ALKBH5 may be efficacious in treating lung fibrosis.

Dataset Information

YAP1/Twist promotes fibroblast activation and lung fibrosis that conferred by miR-15a loss in IPF.

Publications

YAP1/Twist promotes fibroblast activation and lung fibrosis that conferred by miR-15a loss in IPF.

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