Trichostatin A, a histone deacetylase inhibitor, suppresses proliferation and epithelial-mesenchymal transition in retinal pigment epithelium cells.
The proliferation and epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells are the major pathological changes in development of proliferative vitreoretinopathy (PVR), which leads to severe visual impairment. Histone deacetylases (HDACs)-mediated epigenetic mechanisms play important roles in controlling various physiological and pathological events. However, whether HDACs are involved in the regulation of proliferation and EMT in PRE cells remains unidentified. In this study, we evaluated the expression profile of HDAC family (18 genes) and found that some of class I and class II HDACs were up-regulated in transforming growth factor-β2 (TGF-β2)/TGF-β1-stimulated RPE cells. Tricostatin A (TSA), a class I and II HDAC inhibitor, suppressed the proliferation of RPE cells by G1 phase cell cycle arrest through inhibition of cyclin/CDK/p-Rb and induction of p21 and p27. In the meantime, TSA strongly prevented TGF-β2-induced morphological changes and the up-regulation of α-SMA, collagen type I, collagen type IV, fibronectin, Snail and Slug. We also demonstrated that TSA affected not only the canonical Smad signalling pathway but also the non-canonical TGF-β/Akt, MAPK and ERK1/2 pathways. Finally, we found that the underlying mechanism of TSA affects EMT in RPE cells also through down-regulating the Jagged/Notch signalling pathway. Therefore, this study may provide a new insight into the pathogenesis of PVR, and suggests that epigenetic treatment with HDAC inhibitors may have therapeutic value in the prevention and treatment of PVR.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Wei
W
Xiao
Xiaoyun
X
Chen
Xialin
X
Liu
Lixia
L
Luo
Shaobi
S
Ye
Yizhi
Y
Liu
D049109:Cell Proliferation / Q000187:drug effects*; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000254:growth & development*; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage / Q000235:genetics; D053781:Transforming Growth Factor beta2 / Q000008:administration & dosage / Q000235:genetics; D018630:Vitreoretinopathy, Proliferative / Q000235:genetics* / Q000473:pathology
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; C012589:trichostatin A; D006655:Histone Deacetylases
epithelial-mesenchymal transition (EMT); histone deacetylase inhibitor; proliferation; proliferative vitreoretinopathy (PVR); retinal pigment epithelium (RPE) cells