Abstract 4720: Histone deacetylases as promising drug targets for treatment of esophageal squamous cell carcinoma

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and the prognosis for advanced esophageal cancer patients is poor in spite of combination therapy including surgery, chemotherapy and radiotherapy. There is urgent need for the development of new therapeutic agents to improve the prognosis of ESCC patients. To find a lead compound effective for the treatment of ESCC, we first screened a set of 285 compounds (SCADS inhibitor kit available at http://scads.jfcr.or.jp/index.html) for their growth inhibitory effect in 21 cell lines of ESCC. Of the 285 compounds tested, 19 compounds showed greater than 80% growth inhibition at 200 nM in at least one cell line. Our attention was drawn to trichostatin A, a histone deacetylase inhibitor (HDACi), because this compound showed antitumor activity in a broad set of ESCC in this initial screening. Also, this class of compound appears to be a promising agent for the treatment of some type of cancer cells. Therefore, we further explored the underlying mechanism for the antitumor effect of HDACi in ESCC. To validate that HDACs are indeed the molecular targets, HDAC1 or HDAC2 expression was knocked down by siRNA, and the effect on cell growth was examined. Knockdown of HDAC1 or HDAC2 expression alone did not show significant cell growth inhibition, but simultaneous knockdown of HDAC1 and HDAC2 expression induced significant cell growth inhibition. We then evaluated the growth inhibitory effect of two HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and TrichostatinA (TSA), in our panel of 21 ESCC cell lines. The proliferation of ESCC cells was inhibited by SAHA and TSA in a dose-dependent manner. The IC50 of SAHA and TSA for these cell lines ranged from 0.25 to 6.34 microM and 16.1 to 489nM, respectively. The susceptibilities to SAHA and TSA were correlated. Cell cycle analysis by imaging cytometry showed prominent cell-cycle arrest in G2/M phase in cell lines treated with SAHA. Finally, we sought to determine the gene expression pattern associated with the sensitivities to the HDAC inhibitors. Gene expression profiling revealed that a set of genes related to cell cycle or mitosis was highly expressed in cell lines resistant to the HDAC inhibitors. Hierarchial cluster analysis showed that the cell lines were divided into two groups according to the expression pattern of genes related to cell cycle or mitosis, and significant differences were observed in the susceptibility to HDAC inhibitors between the two groups. One group showed high expression of genes involved in G2/M phase and low susceptibility to HDAC inhibitors, and the other group showed the opposite pattern. These results suggest that HDACs may be promising molecular targets for treatment of ESCC and that the susceptibility to HDAC inhibitors may be predicted by the expression pattern of genes involved in cell cycle, especially in the G2/M phase. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4720. doi:1538-7445.AM2012-4720