title: The epigenetic modifier trichostatin A, a histone deacetylase inhibitor, suppresses proliferation and epithelial-mesenchymal transition of lens epithelial cells.
abstract: Proliferation and epithelial-mesenchymal transition (EMT) of lens epithelium cells (LECs) may contribute to anterior subcapsular cataract (ASC) and posterior capsule opacification (PCO), which are important causes of visual impairment. Histone deacetylases (HDACs)-mediated epigenetic mechanism has a central role in controlling cell cycle regulation, cell proliferation and differentiation in a variety of cells and the pathogenesis of some diseases. However, whether HDACs are involved in the regulation of proliferation and EMT in LECs remain unknown. In this study, we evaluated the expression profile of HDAC family (18 genes) and found that class I and II HDACs were upregulated in transforming growth factor β2 (TGFβ2)-induced EMT in human LEC lines SRA01/04 and HLEB3. Tricostatin A (TSA), a class I and II HDAC inhibitor, suppressed the proliferation of LECs by G1 phase cell cycle arrest not only through inhibition of cyclin/CDK complexes and induction of p21 and p27, but also inactivation of the phosphatidylinositol-3-kinase/Akt, p38MAPK and ERK1/2 pathways. Meanwhile, TSA strongly prevented TGFβ2-induced upregulation of fibronectin, collagen type I, collagen type IV, N-cadherin, Snail and Slug. We also demonstrated that the underlying mechanism of TSA affects EMT in LECs through inhibiting the canonical TGFβ/Smad2 and the Jagged/Notch signaling pathways. Finally, we found that TSA completely prevented TGFβ2-induced ASC in the whole lens culture semi-in vivo model. Therefore, this study may provide a new insight into the pathogenesis of ASC and PCO, and suggests that epigenetic treatment with HDAC inhibitors may be a novel therapeutic approach for the prevention and treatment of ASC, PCO and other fibrotic diseases.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, People's Republic of China.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: W
authors.initials: W
authors.lastname: Xiao
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: L
authors.initials: L
authors.lastname: Luo
authors.forename: S
authors.initials: S
authors.lastname: Ye
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D002386:Cataract / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007908:Lens, Crystalline / Q000166:cytology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D051880:Receptors, Notch; C497782:SMAD2 protein, human; C000604407:SNAI1 protein, human; D051899:Smad2 Protein; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053781:Transforming Growth Factor beta2; C012589:trichostatin A; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D006655:Histone Deacetylases