Histone deacetylase inhibitor induction of epithelial–mesenchymal transitions via up-regulation of Snail facilitates cancer progression

Abstract

Histone deacetylase inhibitors (HDACIs) are now emerging as a new class of anticancer drugs. Some of them have been used in clinical treatment for tumors, most impressively in the hematological tumors. But their single-agent activities in epithelial-derived tumors are limited. The mechanisms of these actions of HDACIs are not yet well understood. In this study, it was found for the first time that HDACIs were able to induce epithelial-mesenchymal transitions (EMT) which is believed to trigger tumor cell invasion and metastasis. We show that HDACIs induce fibroblast-like morphology, up-regulate Snail and Vimentin and down-regulate E-cadherin in epithelial cell-derived tumor cell lines. It demonstrates that HDACI treatment enhances further Snail acetylation and reduces its ubiquitylation, and induces Snail transcription as well as Snail nuclear translocation in CNE2 cells. Snail knockdown by siRNAs prevents the change in cell morphology and Vimentin up-regulation in response to HDACIs. The results suggested that Snail plays an important role in the HDACI-induced EMT. It is very crucial for a better understanding of clinical therapeutical failure of HDACIs in the patients with epithelial cell-derived cancers. Therefore, our results indicate that more attention should be paid to the cancer treatment using HDACIs due to the fact that it will enhance the spread risks of cancer cells to facilitate cancer progression and it is very important to select appropriate drugs for different tumors.

Oncogenic roles of Bmi1 and its therapeutic inhibition by histone deacetylase inhibitor in tongue cancer

“…53,54 However, on the other hand, some HDACi unexpectedly triggered EMT program via Snail upregulation in human nasopharyngeal carcinoma cell lines CNE2 and HepG2, and head neck cancer cell lines HN6 and HN13. 52,55 In our study, TSA appeared to paradoxically induce EMT-like changes such as morphological alternation, E-cadherin gain and vimentin loss and enhanced cell motility in tongue cancer cell lines, whereas NaB had no such unexpected capabilities. These findings raise the possibility that some other uncharacterized targets of HDACi independent of Bmi1 may be responsible for these contradictory EMT changes.…”

The epigenetics of epithelial-mesenchymal plasticity in cancer

“…Indeed, the inhibition of HDAC activity has been found to block cell-state transitions in hepatocytes as well as head-and-neck squamous carcinoma cells 109–111 . However, more recent studies have found that HDAC inhibitors can induce an EMT in prostate and nasopharyngeal cancer cells 112,113 . Hence, the utility of these treatments for carcinomas remains unclear and will need to be evaluated carefully.…”

Proteomic Analysis of Epithelial to Mesenchymal Transition (EMT) Reveals Cross-talk between SNAIL and HDAC1 Proteins in Breast Cancer Cells

“…Of note, SNAIL can recruit the Sin3A-HDAC1-HDAC2 complex to the E-cadherin promoter, promoting its repression (54). It was demonstrated that HDAC inactivation can also induce EMT via SNAIL up-regulation, promoting its acetylation and thereby inhibiting its ubiquitination (55). Besides inducing SNAIL up-regulation by post-transcriptional regulation, HDAC1 inhibition can also promote SNAIL transcriptional expression and nuclear translocation (55).…”