Department of Obstetrics/Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Oncogene. 2013 Aug 15;32(33):3896-903. doi: 10.1038/onc.2012.380. Epub 2012 Sep 3.
Ovarian cancer survival rates have stagnated in the last 20 years despite the development of novel chemotherapeutic agents. Modulators of gene expression, such as histone deacetylase (HDAC) inhibitors, are among the new agents being used in clinical trials. Predictors of sensitivity to chemotherapy have remained elusive. In this study, we show that the expression of the transcriptional corepressor C-terminal binding protein-2 (CtBP2) is elevated in human ovarian tumors. Downregulation of CtBP2 expression in ovarian cancer cell lines using short-hairpin RNA strategy suppressed the growth rate and migration of the resultant cancer cells. The knockdown cell lines also showed upregulation of HDAC activity and increased sensitivity to selected HDAC inhibitors. Conversely, forced expression of wild-type CtBP2 in the knockdown cell lines reversed HDAC activity and partially rescued cellular sensitivity to the HDAC inhibitors. We propose that CtBP2 is an ovarian cancer oncogene that regulates gene expression program by modulating HDAC activity. CtBP2 expression may be a surrogate indicator of cellular sensitivity to HDAC inhibitors.
尽管新型化疗药物不断发展，但过去 20 年来卵巢癌的存活率一直停滞不前。表观遗传修饰剂，如组蛋白去乙酰化酶（HDAC）抑制剂，是正在临床试验中使用的新药物之一。但对化疗敏感性的预测因素仍难以捉摸。在这项研究中，我们表明转录共抑制因子 C 端结合蛋白-2（CtBP2）的表达在人类卵巢肿瘤中升高。使用短发夹 RNA 策略下调卵巢癌细胞系中的 CtBP2 表达抑制了所得癌细胞的生长速度和迁移。敲低细胞系还显示出 HDAC 活性的上调和对选定的 HDAC 抑制剂的敏感性增加。相反，在敲低细胞系中强制表达野生型 CtBP2 逆转了 HDAC 活性，并部分挽救了细胞对 HDAC 抑制剂的敏感性。我们提出 CtBP2 是一种卵巢癌癌基因，通过调节 HDAC 活性来调节基因表达程序。CtBP2 表达可能是细胞对 HDAC 抑制剂敏感性的替代指标。
