HDAC9透過活化p300及Smad3參與在TGF-β誘導人類肺纖維母細胞結締組織生長因子表現

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題名:	HDAC9透過活化p300及Smad3參與在TGF-β誘導人類肺纖維母細胞結締組織生長因子表現 HDAC9 mediates TGF-β-induced connective tissue growth factor expression via p300 and Smad3 activation in human lung fibroblasts
作者:	廖能立 LIAO, NENG-LI
貢獻者:	醫學科學研究所碩士班林建煌陳炳常
關鍵詞:	肺部纖維化;TGF-β;HDAC9;p300;Smad3;CTGF lung fibrosis;TGF-β;HDAC9;p300;Smad3;CTGF
日期:	2023-07-13
上傳時間:	2023-12-15 14:05:22 (UTC+8)
摘要:	有許多研究指出，histone deacetylase (HDAC)在肺臟纖維化疾病中扮演重要角色。在bleomycin (BLM)誘導小鼠肺纖維化的動物實驗中，HDAC的抑制有助於減緩纖維化的情形。HDAC9在特發性肺纖維化 (idiopathic pulmonary fibrosis, IPF)病患的肺部組織中過度表現。過量的connective tissue growth factor (CTGF)蛋白在發生肺部纖維化的組織中被認為是加劇疾病進程的主因之一。另外在TGF-β/Smad路徑的活化也已被許多研究證實參與在肺部纖維化的進程中，乙醯化的Smad3在肺部上皮細胞促進上皮細胞間質化 (epithelial-mesenchymal transition, EMT)的發生，進而引發肺部纖維化。p300活化Smad3進而調控轉錄活性則會造成纖維母細胞的分化。我們先前的研究顯示HDAC7可經由活化p300與AP-1調控由ET-1誘導的CTGF表現。但對於HDAC9媒介Smad3乙醯化在肺部纖維母細胞中調控TGF-β誘導CTGF表現的機制目前仍不明確。在本研究中我們發現，在人類肺部纖維母細胞(WI-38)中轉染HDAC9 small interfering (si)RNA可抑制TGF-β誘導的CTGF表現。另外，HDAC9在TGF-β刺激下會由細胞質轉位至細胞核。而轉染p300 siRNA同樣可抑制TGF-β誘導的CTGF表現。同時，Smad3乙醯化程度在TGF-β刺激下會隨著時間增加並在20分鐘時達到高峰。在WI-38細胞中轉染HDAC9或p300 siRNA發現TGF-β誘導的Smad3乙醯化程度被抑制。而TGF-β誘導Smad3轉錄活性同樣也在轉染HDAC9或p300 siRNA後被抑制。此外，TGF-β可促使HDAC9、Smad3及p300互相結合形成複合物並結合至CTGF啟動子區域。從我們以上的研究成果可以得知，TGF-β活化HDAC9並且與p300共同啟動Smad3轉錄活性最終促進CTGF表現。HDAC9在肺部纖維化中扮演重要角色並且可望成為開發治療肺部纖維化藥物的潛力標的。 Many researches have indicated that histone deacetylase (HDAC) play an important role in lung fibrosis. In the animal experiment of bleomycin (BLM)-induced lung fibrosis mice, the inhibition of HDAC were contributed to the ameliorate of lung fibrosis. HDAC9 were overexpressed in the lung of patients with idiopathic pulmonary fibrosis (IPF). The overexpression of connective tissue growth factor (CTGF) protein have been account as the main reason of exacerbate the lung fibrosis process. Furthermore, the activation of TGF-β/Smad pathway also has been reported to participate in lung fibrosis process. The acetylation of Smad3 promotes lung epithelial cells undergo epithelial-mesenchymal transition (EMT) and cause lung fibrosis. The activation of Smad3 by p300 may regulate Smad3 transcription activity in fibroblasts and cause fibroblasts differentiation. Our previous study demonstrated that HDAC7 mediated ET-1-indueced CTGF expression through the activation of p300 and AP-1. However, the mechanism of HDAC9-mediated acetylation of Smad3 in the regulation of the expression of TGF-β-induced CTGF in lung fibroblasts are still unclear. In this study, transfection of HDAC9 small interfering (si)RNA in human lung fibroblasts (WI-38) inhibited TGF-β-induced CTGF expression. TGF-β promoted HDAC9 translocation from the cytosol to nucleus. Transfection of p300 siRNA also reduced TGF-β-induced CTGF expression. Moreover, acetylation of Smad3 was time-dependently increased and reached the maximum at 20 minutes in TGF-β-treated WI-38 cells. Smad3 acetylation was inhibited by transfection of HDAC9 or p300 siRNA. Also, the activity of TGF-β-induced Smad3 transcription activity was suppressed by HDAC9 or p300 siRNA. Furthermore, TGF-β stimulated the formation of HDAC9, Smad3, and p300 complex and recruitment of the complex to the CTGF promoter region. In conclusion, TGF-β activates HDAC9 to initiate Smad3 transcriptional activity by recruiting p300 and eventually promotes the production of CTGF. HDAC9 might play an important role in lung fibrosis and have the potential to be developed as a therapeutic target.
描述:	碩士指導教授:林建煌共同指導教授:陳炳常委員:許銘仁委員:蕭哲志委員:黃聰龍委員:陳炳常委員:林建煌
資料類型:	thesis
顯示於類別:	[醫學科學研究所] 博碩士論文

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