Understanding the regulation of transcription factor SP1 via Wnt and Hippo signaling pathways in colon development and cancer

Abstract

Wnt/β-catenin signaling is a highly conserved pathway found in various multicellular organisms. It plays a crucial role in a myriad of cellular processes necessary for both development and homeostasis during adulthood. Dysregulation of Wnt signaling causes diseases, with colorectal cancer (CRC) being one of the most common outcomes. Previously, we demonstrated that the transcription factor SP1 is an integral component of the Wnt/β-catenin pathway and interacts with β-catenin in the context of CRC. In order to gain a deeper understanding of the broader implications of this complex in relation to development and disease, we performed transcriptome analysis upon transient depletion of both SP1 and β-catenin. Remarkably, the set of genes co-regulated by the SP1:β-catenin complex was particularly enriched in functions related to cell cycle and DNA replication. These functions are essential for normal cell proliferation, which, when disrupted, can contribute to the development of cancer. In CRC patient datasets, we also identified a similar set of target genes displaying dysregulation, reinforcing our initial findings. Furthermore, through experiments involving a xenograft model in mice as well as ectopic overexpression in zebrafish larvae, we observed a synergistic effect driven by the SP1:β-catenin axis. This suggests a conserved role of the SP1:β-catenin complex in promoting cell proliferation during development as well as intestinal homeostasis in adults. To delve deeper, we explored the regulation involving SP1 and Hippo pathway effector YAP. YAP is a component of the Wnt destruction complex and has the ability to regulate the stability of β-catenin. We show that SP1 and YAP can physically interact and positively regulate each other. Notably, the stabilisation of YAP upon Wnt activation is dependent on SP1. In summary, our findings underscore the crucial role of SP1 as a vital regulator essential for the stabilising Wnt-dependent effector proteins, namely β-catenin and YAP.