Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Apr 28:420:1-13.
doi: 10.1016/j.canlet.2018.01.068. Epub 2018 Jan 31.

Histone deacetylase inhibitors upregulate Snail via Smad2/3 phosphorylation and stabilization of Snail to promote metastasis of hepatoma cells

Wei Xu  1 , Hao Liu  2 , Zhi-Gang Liu  3 , Hong-Sheng Wang  4 , Fan Zhang  5 , Hao Wang  6 , Ji Zhang  7 , Jing-Jing Chen  8 , Hong-Jun Huang  9 , Yuan Tan  9 , Meng-Ting Cao  7 , Jun Du  4 , Qiu-Gui Zhang  10 , Guan-Min Jiang  11
Affiliations

Histone deacetylase inhibitors upregulate Snail via Smad2/3 phosphorylation and stabilization of Snail to promote metastasis of hepatoma cells

Wei Xu et al. Cancer Lett. .

Abstract

Hepatocellular carcinoma (HCC) remains the third most common cause of cancer-related mortality. Resection and transplantation are the only curative treatments available, but are greatly hampered by high recurrence rates. Histone deacetylase inhibitors (HDACIs) are considered to be promising anticancer agents in drug development. Currently, four HDACIs have been granted Food and Drug Administration (FDA) approval for cancer. HDACIs have shown significant efficacy in hematological malignancies. However, they have limited effects in epithelial cell-derived cancers, including HCC, and the mechanisms of these are not elucidated. In this study, our results demonstrated that HDACIs were able to induce epithelial-mesenchymal transitions (EMT) in hepatoma cells which are believed to trigger tumor cell invasion and metastasis. We found that HDACIs promoted the expression of Snail and Snail-induced EMT was critical for HDACI-initiated invasion and metastasis. We indicated that HDACIs upregulated Snail in two ways. Firstly, HDACIs upregulated Snail at the transcriptional level by promoting Smad2/3 phosphorylation and nuclear translocation, then combined with the promoter to activate the transcription of Snail. Secondly, we showed that HDACIs regulated the stabilization of Snail via upregulating the expression of COP9 signalosome 2 (CSN2), which combined with Snail and exposed its acetylation site, then promoted acetylation of Snail, thereby inhibiting its phosphorylation and ubiquitination to repress the degradation of Snail. All these results highlighted that HDACIs have limited effects in HCC, and the use of HDACIs combined with other targeted strategies to inhibit EMT, which explored in this study is a promising treatment method for treating HCC.

Keywords: Epithelial-mesenchymal transitions; Histone deacetylase inhibitors; Snail stabilization; Transcriptional activation; Tumor metastasis.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Publication types

MeSH terms

LinkOut - more resources