trichostatin-a and Cataract

Histone acetylation plays key roles in gene expression, but its effects on superoxide dismutase 1 (SOD1) expression in senile cataract remains unknown. To address this problem, the study was to investigate the influence of histone acetylation on SOD1 expression and its effects in the pathogenesis of senile cataract. Senile cataract was classified into three types-nuclear cataract (NC), cortical cataract (CC), and posterior subcapsular cataract (SC)-using the Lens Opacities Classification System III. In senile cataracts, SOD1 expression decreased significantly. Both H3 and H4 were deacetylated at -600 bp of the SOD1 promoter of cataract lenses, and hypoacetylated at -1500, -1200, and -900 bp. In hypoacetylated histones, the hypoacetylation pattern differed among the cataracts. In vitro, anacardic acid (AA) significantly reduced H3 and H4 acetylation at the SOD1 promoter, decreased protein expression, and induced cataract formation in rabbits. AA also inhibited HLEC viability and increased cell apoptosis. In contrast, trichostatin A (TSA) was able to efficaciously stop AA's effects on both rabbit lenses and HLECs. Decreased histone acetylation at the SOD1 promoter is associated with declined SOD1 expression in senile cataracts. Histone acetylation plays an essential role in the regulation of SOD1 expression and in the pathogenesis of senile cataracts.

Topics: Acetylation; Adult; Aged; Aged, 80 and over; Anacardic Acids; Animals; Case-Control Studies; Cataract; Cell Survival; Cells, Cultured; Disease Models, Animal; Down-Regulation; Genetic Predisposition to Disease; Histones; Humans; Hydroxamic Acids; Promoter Regions, Genetic; Rabbits; Superoxide Dismutase-1

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.

Topics: Acetylation; Cataract; Cell Cycle Checkpoints; Cell Movement; Cell Proliferation; Epigenesis, Genetic; Epithelial Cells; Epithelial-Mesenchymal Transition; Extracellular Signal-Regulated MAP Kinases; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Lens, Crystalline; MAP Kinase Signaling System; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Notch; Smad2 Protein; Snail Family Transcription Factors; Transcription Factors; Transforming Growth Factor beta2; Up-Regulation