Abstract:
Tumor development and metastasis involves programmed and progressive changes in expression of large number of genes. The precise molecular mechanisms and signaling pathways regulating the expression of these genes are poorly understood. The chromatin organizer SATB1 acts as molecular switch to regulate a repertoire of genes involved in various developmental processes and diseases. Here, we show that SATB1 is overexpressed in colorectal tumors and correlates with aggressive phenotype of colorectal cancer cells. SATB1 is sufficient to regulate the expression of β-catenin, TCF7L2, multiple downstream effectors and mediators of WNT pathway. SATB1 potentiates expression of key cancer associated genes in non-aggressive colorectal cells, promotes their aggressive phenotype and tumorigenesis in vivo. Conversely, depletion of SATB1 from aggressive cells reprograms the expression of cancer associated genes, reverses their cancer phenotype and their potential to develop tumors in vivo. SATB1 and β-catenin bind to promoters of Wnt target genes and regulate their expression. Interestingly, SATB1 expression is triggered upon hyperactivation of Wnt/β-catenin signaling and is repressed upon TCF7L2 and β-catenin depletion. Promoter analysis revealed multiple sites for TCF7L2 on SATB1 promoter and direct binding of TCF7L2/β-catenin complex responsible for induction and regulation of SATB1. Furthermore, SATB1 shares feedback regulatory network with TCF7L2/β-catenin signaling and is required for Wnt dependent regulation of β-catenin. We also show that specific protein 1 (SP1) is required for Wnt/ β-catenin signaling-dependent regulation of SATB1. We provide various biochemical evidences that β-catenin interacts with SP1 and stabilizes it at protein level. The SP1/ β-catenin complex binds to SATB1 promoter thereby directly regulates SATB1 expression in Wnt-dependent manner. Collectively, these results provide unequivocal evidence to establish that SATB1, a novel target of Wnt/SP1 signaling, reprograms the expression of tumor growth and metastasis associated genes to promote tumorigenesis and functionally overlaps with Wnt signaling.
