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.
Highlights
The growing body of evidence shows that proliferation and epithelial–mesenchymal transition (EMT) of lens epithelial cells (LECs) are the major pathologic changes in development of ASC6,7 and posterior capsule opacification (PCO).[8,9] Transforming growth factor b (TGFb), especially TGFb2, the major isoform in the aqueous humor of the eye, is the most important factor driving the transdifferentiation and pathologic fibrosis of LECs.[10]
These results suggest that several family members of class I and II Histone deacetylases (HDACs) are upregulated in TGFb2-induced EMT in LECs
These results suggest that tricostatin A (TSA) inhibits the proliferation of LEC lines SRA01/04 and HLEB3 by G1 phase cell cycle arrest through inhibition of cyclin D1/CDK4/6 and cyclin E1/CDK2 complexes, and induction of P21 and P27
Summary
The growing body of evidence shows that proliferation and epithelial–mesenchymal transition (EMT) of lens epithelial cells (LECs) are the major pathologic changes in development of ASC6,7 and PCO.[8,9] Transforming growth factor b (TGFb), especially TGFb2, the major isoform in the aqueous humor of the eye, is the most important factor driving the transdifferentiation and pathologic fibrosis of LECs.[10]. ASC is a primary cataract, which is caused by the proliferation and EMT of LECs in situ These fibroblasts form subcapsular plaques beneath the lens capsule, and similar to the transdifferentiated cells in PCO.[2] Based on the above observations, inhibition of LECs proliferation, migration and TGFb-induced EMT may be a promising strategy to prevent ASC and PCO. Inhibition of HDAC activity with TSA strongly suppressed proliferation and TGFb2-induced EMT of LECs. we demonstrated that TSA completely prevented TGFb2-induced ASC in the whole lens culture semi-in vivo model. We demonstrated that TSA completely prevented TGFb2-induced ASC in the whole lens culture semi-in vivo model
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