Abstract 2290: A novel function in metastasis for YY1 overexpression in the initiation of the EMT phenotype

Abstract

Abstract Metastasis is the main cause of death in cancer patients. The underlying molecular mechanisms of the metastatic process and their regulation in different malignancies are unknown. Survival pathways, such as the constitutively activated NF-κB pathway, contribute to the initiation of metastasis, a process known as epithelial to mesenchymal transition (EMT). The EMT phenotype is characterized by several gene modifications such as inhibition of epithelial gene products (e.g. E-cadherin, cytokeratin 18) and upregulation of mesenchymal gene products (e.g. vimentin and fibronectin). In addition, the cells exhibit invasive properties. The metastasis-inducer transcription factor, Snail, is intimately involved in EMT and is transcriptionally regulated, in part, by NF-κB. A recent report demonstrated that Snail is transcriptionally regulated, in part, by the transcription factor Yin Yang 1 (YY1) and YY1 is downstream of NF-κB. We have reported that YY1 expression is a prognostic marker in prostate cancer and YY1 also regulates tumor cell resistance to apoptosis by cytotoxic therapeutics. Based on these findings, we hypothesized that the expression levels of YY1 in cancer may also regulate EMT directly and/or indirectly through its regulation of Snail transcription. This hypothesis was tested using the human metastatic prostate carcinoma cell lines, PC-3 and DU-145, that exhibit the EMT phenotype as models. The relationship between inhibition of YY1 and inhibition of EMT was established by several lines of evidence. Treatment of the tumor cells with the proteasome inhibitors, NPI-0052 or Bortezomib, inhibited NF-κB, Snail and YY1 activities and correlated with inhibition of EMT. The direct role of YY1 expression and activity in the regulation of EMT was shown by treating cells with YY1 siRNA and resulting in the inhibition of the EMT phenotype. In turn, inhibition of Snail resulted in upregulation of the expression of the metastasis-suppressor/immune surveillance cancer gene product, Raf-1 kinase inhibitor protein (RKIP). The upregulation of RKIP by YY1 siRNA was due to the inhibition of the RKIP transcription repressor Snail. These findings establish a novel role for YY1 in the regulation of EMT. The findings also establish the dysregulation of the circuitry NF-κB/Snail/YY1/RKIP in cancer and metastasis resulting in the initiation of EMT. Further, this dysregulation has also been recently reported by us to regulate tumor cell resistance to apoptotic-inducing stimuli. Therefore, this dysregulated circuitry and downstream regulated gene products may be considered as novel targets for the regulation of both metastasis and resistance. 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 2290.