The novel role of Yin Yang 1 in the regulation of epithelial to mesenchymal transition in cancer via the dysregulated NF-κB/Snail/YY1/RKIP/PTEN Circuitry.

The majority of cancers develop genetic and molecular strategies to resist conventional cytotoxic therapies as well as escape from the host's immune surveillance. These events lead to tumor persistence and spread through activation of the epithelial to mesenchymal transition (EMT) program and metastasis. Expression profiling analysis has revealed various tumor metastasis-inducing and metastasis-suppressing genes that regulate the metastatic process and maintain the microenvironment of the tumor cells. EMT in cancer entails the molecular reprogramming and phenotypic changes that characterize the conversion of immobile cancer epithelial cells to motile mesenchymal cells. A hallmark of EMT is the loss of E-cadherin, the epithelial homotypic adhesion molecule, and gain of mesenchymal markers such as vimentin and fibronectin. The molecular mechanisms underlying the initiation of EMT consist, in part, in the constitutive activation of survival signaling pathways such as the nuclear factor (NF)-κB pathway. The NF-κB pathway has been implicated directly in the regulation of EMT and indirectly through the transcription and expression of several gene products that participate in the EMT cascade, such as Snail, the metastasis-inducer and E-cadherin suppressor transcription factor. In turn, Snail represses the metastasis-suppressor gene product Raf-kinase inhibitor protein (RKIP) that inhibits both the Raf-1/MEK/ERK and NF-κB survival pathways implicated in EMT. Consequently, tumor cells normally exhibit a dysregulated NF-κB/Snail/RKIP circuitry that is intimately involved in the initiation of EMT and maintenance of drug resistance. Additional deregulated gene products in this circuit, such as the metastasis-suppressor phosphatase and tensin homologue (PTEN; repressed by Snail) and the putative-metastasis inducer Yin Yang (YY) 1 (target of NF-κB) also have been associated in the regulation of EMT. We recently have investigated the direct role of YY1 in the regulation of EMT. This review discusses the molecular regulation of EMT in cancer cells through the activity of the dysregulated NF-κB/Snail/ YY1/PTEN/RKIP circuitry. In addition, we propose YY1 as a potential novel prognostic biomarker for EMT and a therapeutic target for both the prevention of metastasis and the reversal of resistance.