These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Pharmacological Targeting of BET Bromodomains Inhibits Lens Fibrosis via Downregulation of MYC Expression.
    Author: Wang X, Wang B, Zhao N, Wang C, Huang M, Chen B, Chen J, Sun Y, Xiong L, Huang S, Liu Y.
    Journal: Invest Ophthalmol Vis Sci; 2019 Nov 01; 60(14):4748-4758. PubMed ID: 31731295.
    Abstract:
    PURPOSE: Lens fibrosis involves aberrant growth, migration, and transforming growth factorβ (TGFβ)-induced epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs). In this study, we investigated the role of the bromo- and extra-terminal domain (BET) inhibitor in lens fibrotic disorder to identify drug-based therapies. METHODS: Rat lens explants, rabbit primary lens epithelial cells (rLECs), human lens explants and human SRA01/04 cells were treated with TGFβ2 in the presence or absence of the BET bromodomain inhibitor JQ1 or the MYC inhibitor 10058-F4. Proliferation was determined by MTS assay. Cell migration was measured by wound healing and transwell assays. The expression levels of fibronectin (FN), α-smooth muscle actin (α-SMA), E-cadherin, and phosphorylated downstream Smads were analyzed by Western blot, qRT-PCR, and immunocytochemical experiments. Transcriptome analysis was conducted to explore the molecular mechanism. RESULTS: Blockage of BET bromodomains with JQ1 significantly suppressed rLECs proliferation by inducing G1 cell cycle arrest. Furthermore, JQ1 attenuated TGFβ2-dependent upregulation of mesenchymal gene expression and phosphorylation of Smad2/3 during the progression of EMT, whereas E-cadherin expression was preserved. JQ1 repressed MYC expression, which was dose- and time-dependently upregulated by TGFβ2. Inhibiting MYC with either the small-molecule inhibitor 10058-F4 or genetic knockdown phenocopied the effects of JQ1 treatment. MYC overexpression partially reversed the JQ1-regulated EMT-related alteration of gene expression. Both JQ1 and 10058-F4 blocked the expression of TGFβ receptor II and integrin αv in rLECs and abolished TGFβ2-induced opacification and subcapsular plaque formation in rat lens explants. CONCLUSIONS: Our results demonstrate the antifibrotic role of JQ1 in maintaining the epithelial characteristics of LECs and blocking TGFβ2-induced EMT, possibly by downregulating MYC, thereby providing new avenues for treating lens fibrosis.
    [Abstract] [Full Text] [Related] [New Search]