Twist is a highly conserved basic helix-loop-helix transcription factor and plays a pivotal role during the development. Mutations in this gene have been found in patients with Saethre-Chotzen syndrome. Recent studies have shown up-regulation of Twist in melanoma, T-cell lymphoma and carcinomas of stomach prostate and breast. Twist is a key factor responsible for metastasis of breast cancer by promoting epithelial-to-mesenchymal transition. In addition, elevated levels of Twist are associated with Texol resistance. However, the underlying molecular mechanism and involvement of Twist in human ovarian cancer have not been well documented. In this study, we analyzed transcript profiles of Twist using Affymetrix array H133A plus 2.0. in doxycycline-inducible Twist-HeLa cells. Among 275 genes that are changed in both 6 h and 12 h time points, a group of pro-apoptotic genes, such as BAX, TNFRSF19, BNIP3L, are downregulated, whereas a number of pro-survival genes are induced including MCL-1, EGFR and IGF-1. These results were confirmed by quantitative RT-PCR and/or immunoblotting. Further, we demonstrate frequent overexpression of Twist in ovarian cancer cell lines (45%; 5/11) and primary tumors (48.5%; 34/70). To our surprise, unlike breast and prostate cancer, the majority of the ovarian tumors exhibiting elevated protein levels of Twist are early stage and low grade. In addition, knockdown of Twist in cisplatin resistant ovarian cell lines C13 and A2780CP sensitizes cells to cisplatin treatment through the activation of apoptotic pathway. These findings indicate that Twist exerts cell survival function by transcriptional regulation of apoptosis-associated genes and that upregulation of Twist is a common occurrence in human ovarian cancer and could play an important role in ovarian carcinogenesis.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]