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

Authors Geng Y, Liu J, Xie Y, Jiang H, Zuo K, Li T, Liu Z

Received 5 March 2018

Accepted for publication 16 May 2018

Published 28 August 2018 Volume 2018:10 Pages 2905—2914


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Antonella D'Anneo

Yan Geng,1,* Jing Liu,2,* Ying Xie,2 Hongmei Jiang,2 Kai Zuo,3 Tao Li,4 Zhiqiang Liu2

1Department of Clinical Laboratory, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi, 030012 China; 2Department of Physiology and Pathophysiology, Tianjin Medical University, Heping, Tianjin, 300070 China; 3Department of Infectious Disease, Binzhou People’s Hospital, Binzhou, Shandong, 264000 China; 4Department of Immunology, School of Medicine, Hunan Normal University, Changsha, Hunan, 410013, China

*These authors contributed equally to this work

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 immunofluorescence, 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.

Keywords: histone deacetylase, trichostatin A, multiple myeloma, hedgehog signaling

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