In addition, human Snail2 (Slug) and mouse Snail1 amino Selleckchem Enzalutamide acid sequences are shown for comparison to the human Snail1 sequence. Human Slug is 48% identical to human Snail1, and mouse Snail1 is 88% identical to human Snail1. The sequence alignments were run through BLAST [9]. Epithelial-to-mesenchymal transition (EMT) is the process by which epithelial cells lose their apical polarity and adopt a mesenchymal phenotype, thereby, increasing migratory properties, invasiveness and apoptotic

resistance. The expression of mesenchymal markers, like vimentin and fibronectin, replaces that of the usual epithelial markers, including E-cadherin, cytokeratins and Mucin-1 [10]. EMT is fundamental to both normal developmental processes and metastatic cancer. The induction of epithelial-to-mesenchymal transition (EMT) is Snail1’s most studied function, as this process is crucial for the formation of the mesoderm and the neural crest [1]. Snail1 knockout in mice is lethal because gastrulation does not occur [11]. The primary mechanism of Snail1-induced EMT is the repression of E-cadherin, which causes reduced cell adhesion and promotes migratory capacity [12]. The further elucidation of Snail1’s role in EMT selleck products provides a critical insight into the development of metastatic cancer. In addition, Snail1 has been recently implicated in the regulation

of drug/immune resistance and the cancer stem cell (CSC) phenotype [13–16]. Regulation of Snail1 expression Transcriptional regulation The Notch intracellular domain, LOXL2, NF-κB, HIF-1α, IKKα, SMAD, HMGA2, Egr-1, PARP-1, STAT3, MTA3, and Gli1 all interact directly with the Snail1 promoter to regulate Snail1 at isometheptene the transcriptional level [17–29]. Hypoxic stress, caused by insufficient oxygen, prompts a transcriptional response mediated by hypoxia-inducible factors (HIFs) [17]. Notch

increases HIF-1α recruitment to the LOX promoter, and LOXL2 oxidizes K98 and/or K127 on the Snail1 promoter, leading to a conformational change in shape [18]. Under hypoxic conditions, HIF-1α binds to HRE2, contained within -750 to -643 bp of the Snail1 promoter, and increases Snail1 transcription. Knockdown of HIF-1α results in the repression of both Snail1 and EMT [19]. NF-κB also binds to the Snail1 promoter, between -194 and -78 bp, and increases its transcription [20]. SMAD2 and IKKα bind concurrently to the Snail1 promoter between -631 and -506 bp, resulting in Snail1’s upregulation [21]. HMGA2 cooperates in this complex as well, as the binding of HMGA2 to the Snail1 promoter increases SMAD binding [22]. In addition, ILK promotes PARP-1 binding, and STAT3 binds as a final result of an IL-6/JAK/STAT pathway [23,24]. In mice, a pathway beginning with HB-EGF and progressing through the MEK/ERK pathway has also induced STAT3 binding to the Snail1 promoter [25]. Gli1 and Snail1 interact through a positive feedback loop: Shh and Wnt crosstalk results in the upregulation of both [26].