eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
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SCImago Journal & Country Rank
1/2019
vol. 15
 
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abstract:
Basic research

Trichostatin A activates FOXO1 and induces autophagy in osteosarcoma

Yunjuan Bai, Yun Chen, Xiaochen Chen, Jiukun Jiang, Xiao Wang, Liping Wang, Jigang Wang, Jianbin Zhang, Liang Gao

Arch Med Sci 2019; 15, 1: 204–213
Online publish date: 2018/03/02
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Introduction
Histone deacetylase inhibitors (HDACIs) inhibit human osteosarcoma growth and cause apoptosis. Previously, we reported that HDACIs induce autophagy via the FOXO1 pathway. Whether there is involvement of autophagy in anti-osteosarcoma activity of HDACIs is still unknown.

Material and methods
Confocal microscopy was performed to determine the formation of GFP-LC3 puncta. Western blotting was conducted to measure FOXO1, and autophagy-related protein levels. Small interference RNA (siRNA) specific for FOXO1 was transfected into U2OS cells to knock down FOXO1 expression level. Flow cytometry was performed to quantify cell death.

Results
In this study, we first observed that trichostatin A (TSA) induces autophagy in human osteosarcoma cells. Moreover, we found that TSA treatment inhibits the mammalian target of rapamycin (mTOR) signaling pathway and enhances forkhead box O1 (FOXO1) transcriptional activity, which is responsible for the increased autophagy level, while suppression of FOXO1 function by siRNA knockdown markedly decreases TSA-induced autophagy.

Conclusions
We found that inhibition of autophagy, either by autophagy inhibitors or ATG gene knockdown, markedly enhances TSA-caused cell death. Taken together, our studies reveal the function of autophagy in HDACI-caused osteosarcoma cell death and thus support the development of a novel therapeutic strategy by combining HDACIs and autophagy inhibitors in osteosarcoma treatment.

keywords:

trichostatin A, autophagy, forkhead box O1, mammalian target of rapamycin

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