Abstract 742: Up-regulation of histone deacetylases in colon cancer.

Abstract

Abstract The reversible acetylation of histones and non-histone proteins by histone acetyltransferases (HATs) and deacetylases (HDACs) play critical roles in transcriptional regulation in eukaryotic cells. Acetylation of histones is commonly associated with transcriptional activation of genes, and is thought to be responsible for the formation of a local “open chromatin” structure. In contrast, removal of acetyl groups by histone deacetylases (HDACs) frequently accompanies suppression of gene activity. Mammalian HDACs are classified into four classes (I, II, III and IV) based on the sequence homology to the yeast histone deacetylases Rpd3 (reduced potassium dependency), Hda1 (histone deacetylase1), and Sir2 (silent information regulator 2), respectively. Although the precise cellular functions of the different HDAC enzymes are still poorly understood, evidence suggests that different members of the HDAC family have distinct functions. It had been shown that overexpression of class I HDACs are more relevant to cancer development in many cancer types. In the absence of class I HDACs, cancer cells arrest either at the G1 phase of the cell cycle or the G2/M transition, resulting in the loss of mitotic cells, cell growth inhibition, and an increase in the percentage of apoptotic cells. Therefore, HDAC inhibitors had been used as a class of chemotherapeutic agents in cancer treatment. However, little is known about factors involved in regulation of class I expression in cancer cells. Our study focuses on the regulation of HDAC1 and 2 expressions in colon cancer cells. We found that compared with normal colon cell lines, both mRNA and protein level of HDAC1 and HDAC2 are higher in colon cancer cells, which suggests that HDAC1/2 is regulated at transcriptional level in colon cancer. HDAC1 and HDAC2 promoters were cloned and the promoter reporter activity was studied. Our result shows that HDAC1 and 2 promoters are highly active in colon cancer cells. Through mutation study on various putative transcription factors binding sites, we found that promoter activity is regulated by transcription factor Sp1/Sp3, which are also elevated in colon cancer cells lines and tissues. Chromatin immunoprecipitation assay also indicate that Sp1/Sp3 is recruited to HDAC1/HDAC2 promoter. Inhibition of Sp1/Sp3 through inhibitor or shRNA decreased HDAC1/2 expression and reduced cell proliferation. These results indicate that Sp1/Sp3 may be major regulators for HDAC1 and HDAC2 overexpression in colon cancer and this finding may shed light on future treatment of colon cancer. Citation Format: Hui Yang, Tal Salz, Maria Zajac-kaye, Daiqing Liao, Suming Huang, Yi Qiu. Up-regulation of histone deacetylases in colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 742. doi:10.1158/1538-7445.AM2013-742