The Mechanism Of Trichostatin A Promoting Migration Of Esophageal Squamous Carcinoma Cells

Background With the advancement of medical level,molecular targeted therapy has gradually become a new method for the treatment of tumor,especially suitable for patients with advanced stage.Histone deacetylase(HDAC)inhibitors as a new class of targeted antitumor drugs,promote the transcription of tumor suppressor genes and exert powerful antitumor effect by inhibiting HDAC activity.However,in recent years,it has been reported that HDAC inhibitors promote the migration and invasion in certain tumors such as lung cancer,prostate cancer and breast cancer.Previous studies have found that HDAC inhibitors can inhibit the proliferation of esophageal squamous cell carcinoma(ESCC)cells,but the effect of HDAC inhibitors on ESCC cells migration is unclear.Objective Clarify the effect of HDAC inhibitor Trichostatin A(TSA)on ESCC cells migration and the possible mechanism,the results will provide a theoretical basis for the rational application of clinical anticancer drugs.Methods Two ESCC cell lines,namely KYSE-150,EC9706 were used.Firstly,the effect of TSA on ESCC cells migration were detected by Transwell experiment.Secondly,Western blot was used to detect the expression of epithelial-mesenchymal transition(EMT)related markers and histone H3K9 acetylation(H3K9Ac).Thirdly,by transfection of small interfering RNA slug(si-Slug)and detect the effect of TSA on ESCC cells migration with knock down Slug by Transwell experiment,detect EMT related proteins by Western blot.Finally,ESCC cells were treated with ERK inhibitors(U0126,PD98059),PAI-1 inhibitor(PAI-039),BRD4 inhibitor(JQ1),and their effects on TSA induces ESCC cells migration were examined.Results TSA enhances the migration capacity of ESCC cells significantly;Western blot result showed that TSA reduces the expression of EMT associated protein E-cadherin,increases the expression of ?-catenin,Vimentin and Slug,meanwhile increases the phosphorylation of ERK1/2(p-ERK1/2).Knock down Slug inhibits the migration and the EMT of ESCC cells that induced by TSA.U0126 inhibits the migration and the expression of PAI-1 that induced by TSA.PAI-1 inhibitor PAI-039 inhibits the migration and EMT of ESCC cells that induced by TSA.But the inhibitor does not affect the expression of Slug.Histone acetylation recruits BRD4,and its inhibitor JQ1 reverses the expression of p-ERK1/2 and PAI-1 proteins that induced by TSA,inhibits the migration and EMT of ESCC cells that induced by TSA.Conclusions(1)TSA promotes Slug transcription,induces EMT and enhances the migration ability of ESCC cells;(2)TSA activates BRD4/ERK/Slug and BRD4/ERK/PAI-1,enhances the migration of ESCC cells.