Purpose: Posterior capsule opacification (PCO) after cataract surgery is due in part to proliferation of the adhering lens epithelial cells and transdifferentiation into mesenchymal cells. The histone deacetylase (HDAC) inhibitors, trichostatin A (TSA) and vorinostat (suberoylanilidehydroxamic acid [SAHA]) are known to modulate cell proliferation and epithelial-mesenchymal transition (EMT). Studies have shown that TGFβ2 can induce EMT similar to that seen during PCO. This study evaluated the effects of TSA and SAHA on TGFβ2-induced EMT in lens epithelial explants.
Methods: Epithelial cells adherent to lens capsules were isolated from fresh pig lenses and human donor lenses and cultured for 12 hours. Explants were pretreated with TSA or SAHA for 1 hour and then treated with TGFβ2 for up to 3 days. Scratch wound healing assay was used to determine epithelial cell proliferation and migration in the samples. The effects of TSA and SAHA on histone acetylation and HDAC 1 to 6 levels were analyzed by Western blotting.
Results: Western blotting and immunocytochemistry demonstrated high expression of α-SMA in lens epithelial cells treated with TGFβ2. The HDAC inhibitors exerted dose-dependent inhibition of α-SMA expression, with complete inhibition occurring with 0.5 μM of TSA and 2.5 μM of SAHA. Transforming growth factor β2-induced EMT was suppressed by TSA and SAHA. Histone deacetylase inhibition in pig lens epithelia led to increased acetylation of histone 3 and 4 at multiple sites.
Conclusions: Histone deacetylase inhibitors, TSA, and SAHA prevent EMT in lens epithelial explants. The results also suggest that the epigenetic modifiers are the potential targets to control PCO after cataract surgery.
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http://dx.doi.org/10.1167/iovs.14-14109 | DOI Listing |
Nat Commun
November 2024
Department Synthetic and Structural Biochemistry, Institute of Biochemistry, University of Greifswald, Greifswald, Germany.
Classical Zn-dependent deac(et)ylases play fundamental regulatory roles in life and are well characterized in eukaryotes regarding their structures, substrates and physiological roles. In bacteria, however, classical deacylases are less well understood. We construct a Generalized Profile (GP) and identify thousands of uncharacterized classical deacylases in bacteria, which are grouped into five clusters.
View Article and Find Full Text PDFBiol Pharm Bull
October 2024
Zhejiang Key Laboratory of Geriatrics and Geriatrics Institute of Zhejiang Province, Zhejiang Hospital.
Castration-resistant prostate cancer (CRPC) contributes mostly to prostate cancer-specific mortality, and conventional castration therapy is almost ineffective, new therapies are needed. As a new potential anti-cancer drug, histone deacetylases (HDACs) inhibitors were demonstrated to be effective in inhibiting drug-resistance cancers in preclinical studies, but the results from clinical trials on CRPC patients were disappointing, and the reasons are unknown. In this study, we investigated the effect of suberanilohydroxamic acid (SAHA), a broad-spectrum pan-HDAC inhibitor, on proliferation, apoptosis, cell cycle progression in PC3 cells, and found that, unlike significant inhibiting effects at high-dose, low-dose SAHA significantly promoted PC3 cell growth.
View Article and Find Full Text PDFACS Med Chem Lett
September 2024
Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Via Belmeloro 6, Bologna 40126, Italy.
Epigenetics
December 2024
Department of Chemical and Biological Sciences, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, SP, Brazil.
In Silico Pharmacol
May 2024
Department of Clinical Pharmacology, JIPMER, Puducherry, India.
Unlabelled: Chemotherapy is one of the most well-established and effective cancer treatments available. However, non-tumor-associated damage restrict the treatment's effectiveness and safety. Our growing understanding of cancer epigenetics has resulted in new therapeutic options and the potential of better patient outcomes in recent decades.
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