Trichostatin A promotes GLI1 degradation and P21 expression in multiple myeloma cells

Abstract

Background: Histone deacetylase inhibitors are promising drugs for the future application in cancer therapy. Trichostatin A (TSA), a histone deacetylase inhibitor, exhibits effective antitumor effects in various cancers. However, the effects and underlying mechanisms of TSA on multiple myeloma (MM) are not fully investigated. Methods: In the present study, RPMI8226 and MM.1S cells treated with TSA were used for cell proliferation, cell cycle, and survival examinations, then the localization and post transcriptional modification of GLI1 protein as well as the target gene P21 were analyzed using immunofluo-rescence, immunoprecipitation, western blots and qPCR, respectively. Results: TSA exerted a time and dose-dependent cytotoxicity on MM cell lines, and suppressed the proliferation of MM cells and induced an upregulation of p21 protein accompanied by a decreased expression of cyclin D1. TSA treatment led to a downregulation of GLI1, and the nuclear accumulation of GLI1 was also inhibited. As a result of hedgehog inhibition, the expression of MYC and SURVIVIN was greatly weakened after TSA treatment. Furthermore, TSA accelerated GLI1 degradation in a proteasome-dependent manner. Additionally, p21 induction also contributed to GLI1 downregulation via reducing the transcription of GLI in mRNA level. Rescue experiments verified that exogenous expression of GLI1 alleviated MM cell apoptosis induced by TSA. Conclusion: These results indicated that TSA represses MM cell growth and induces cell apoptosis. The inhibition of hedgehog signaling is an important mechanism accounting for the cytotoxic effects of TSA.