Abstract
The process of epithelial-mesenchymal transition (EMT) is associated with tumor progression. Tumor cells that undergo EMT have altered morphology and acquire a stem cell phenotype. Although there are numerous studies that demonstrate that shRNA approaches targeting specific transcription factors can block EMT, there are few pharmacological agents yet identified that can alter the process of EMT. Recent evidence suggests that the silencing of E-cadherin during EMT is dependent upon the activity of specific histone deacetylyase enzymes, which are known to regulate gene transcription. We used Tera-2 (HTB 106) embryonal carcinoma cells grown as 3 dimensional spheroids as a model of a tumor type characterized by a cancer stem cell phenotype. We observed that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat; Zolinza®, Merck), which is FDA approved for treatment of cutaneous T cell lymphoma, significantly inhibited expression of over 55 distinct genes associated with EMT including those regulating responses to growth factors, adhesion, motility, and genes associated with maintenance/survival of stem cells, including Alpha 5 Integrin/fibronectin receptor alpha (ITGA5), Caldesmon 1 (CALD1), Epidermal growth factor receptor (EGFR), Forkhead box C2 (MFH-1, mesenchyme forkhead 1) (FOXC2), Glycogen synthase kinase 3 beta (GSK3 beta), Jagged 1 (JAG1), Integrin-linked kinase (ILK), Matrix metallopeptidase 2 (MMP2), Notch 1 homolog (NOTCH1), Platelet-derived growth factor receptor beta (PDGFb), Snail homolog 1 (SNAI1), Snail homolog 2 (SNAI2), Transcription factor 4 (TCF4), transforming growth factorβ1 (TGFβ1), Twist homolog 1 (Twist1), Wingless-type MMTC integration site family, member 5b (WNT5b), and Zinc finger E-box binding homeobox 2 (ZEB2). SAHA also altered the morphology of Tera-2 cells when cultured as adherent cells, which was associated with inhibited of both invasion, and anchorage independent growth in soft agar. In addition, SAHA inhibited the self-renewal capacity of Tera-2 tumor spheroids, which was associated with changes in expression of stem cell surface markers. Studies are ongoing to identify the HDAC enzymes that regulate expression of genes associated with the process of EMT and maintenance/survival of Tera-2 tumor spheroids that are targeted by SAHA. These studies suggest that HDAC inhibitors may be promising agents to reverse the process of EMT and may be potentially effective as inhibitors of tumor progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1465.