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

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.

Curcumin downregulates the expression of Snail via suppressing Smad2 pathway to inhibit TGF-ß1-induced epithelial-mesenchymal transitions in hepatoma cells.

Hepatocellular carcinoma (HCC) remains the third cause of cancer-related mortality. Resection and transplantation are the only curative treatments available but are greatly hampered by high recurrence rates and development of metastasis, the initiation of cancer metastasis requires migration and invasion of cells, which is enabled by epithelial-mesenchymal transitions (EMT). TGF-ß1 is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation and apoptosis. TGF-ß1 is known as a major inducer of EMT, and it was reported that TGF-ß1 induced EMT via Smad-dependent and Smad-independent pathways. However, the extrinsic signals of TGF-ß1 regulated the EMT in hepatoma cells remains to be elucidated, and searching drugs to inhibit TGF-ß1 induced EMT may be considered to be a potentially effective therapeutic strategy in HCC. Fortunately, in this study, we found that curcumin inhibited TGF-ß1-induced EMT in hepatoma cells. Furthermore, we demonstrated that curcumin inhibited TGF-ß1-induced EMT via inhibiting Smad2 phosphorylation and nuclear translocation, then suppressing Smad2 combined with the promoter of Snail which inhibited the transcriptional expression of Snail. These findings suggesting curcumin could be a useful agent for antitumor therapy and also a promising drug combined with other strategies to preventing and treating HCC.

Curcumin combined with FAPαc vaccine elicits effective antitumor response by targeting indolamine-2,3-dioxygenase and inhibiting EMT induced by TNF-α in melanoma.

Fibroblast activation protein α (FAPα) is a potential target for cancer therapy. However, elimination of FAPα+ fibroblasts activates secretion of IFN-γ and TNF-α. IFN-γ can in turn induce expression indolamine-2,3-dioxygenase (IDO), thereby contributing to immunosuppression, while TNF-α can induce EMT. These two reactive effects would limit the efficacy of a tumor vaccine. We found that curcumin can inhibit IDO expression and TNF-α-induced EMT. Moreover, FAPαc vaccine and CpG combined with curcumin lavage inhibited tumor growth and prolonged the survival of mice implanted with melanoma cells. The combination of FAPαc vaccine, CpG and curcumin stimulated FAPα antibody production and CD8+ T cell-mediated killing of FAPα-expressing stromal cells without adverse reactive effects. We suggest a combination of curcumin and FAPαc vaccine for melanoma therapy.