Inhibitor Of Bet Targets YAP Signaling Pathway And Regulates The Proliferation Of Chondrosarcoma Cells

Purpose:Chondrosarcoma,the second-most frequent primary bone malignancy,is generally more resistant to conventional chemotherapy and radiotherapy.Surgical resection is the most acceptedable treating approach for chondrosarcoma;however,a large amount of patients develops resistant and even recurrent.Therefore,the development of an effective adjuvant therapy is necessary.Recently,targeting the epigenetic regulator such as bromodomain and extraterminal domain(BET)proteins has achieved great success.For instance,the bromodomain inhibitor JQ1 has been shown to inhibit the growth of several cancer cells both in vitro and in vivo.Methods:CKK-8 assay was used to determine the inhibitory rate of JQ1 on chondrosarcoma cells,colony formation assay was used to determine the colony growth of chondrosaroma in the presence of JQ1 treatment.Flow cytometry was used to evaluate the cell cycle and apoptosis.Confocal microscopy was used to observe subcellular localization of c-Myc.Western blotting was used to determine the expression of cell cycle related proteins,c-Myc,Bcl-XL,and the YAP signaling pathway.Immunohistochemistry was used to detect the expression of YAP in microtissue array of chondrosarcoma.Results:Herein we demonstrated that JQ1 significantly inhibited chondrosarcoma cell growth and colony formation.JQ1 also induced marked G1-phase cell cycle arrest coincided with the up-regulation of p21WAF1/CIP1,p27Kip1,and Cyclin D1 expression,and the down-regulation of Cyclin E2 expression.Moreover,JQ1 induced the premature senescence of SW 1353 cells,and that prolong treatment of JQ1 caused cell apoptosis.Mechanistically,the JQ1-induced cell growth inhibition was correlated with the suppression of c-Myc and Bcl-x L,which are the prime genes for cell cycle control and anti-apoptosis.Further,we demonstrated that p21 negatively regulated the expression of c-Myc and Bcl-x L upon JQ1 treatment,and that the growth inhibition of SW 1353 and Hs 819.T cells and induction of p21 were predominantly regulated by the LATS1/YAP signaling but not through a p53-dependent manner.Last,we also found that YAP is overexpressed in chondrosarcoma tissue and correlates with disease progression.Conclusion: we disclosed a novel mechanism that JQ1 inhibits cell proliferation,induces cell senescence and apoptosis of chondrosarcoma cells through the regulation of the YAP/p21/c-Myc/Bcl-x L signaling axis.