Positive regulation of β-catenin-PROX1 signaling axis by DBC1 in colon cancer progression

Aberrant activation of Wnt/beta-catenin pathway contributes to colorectal cancer (CRC) progression. However, little is known about regulatory mechanisms of the beta-catenin activity in cancer progression. Here we investigated the role of DBC1, which was recently reported as a negative regulator of SIRT1 and a transcriptional coactivator, in the regulation of Wnt/beta-catenin signaling. We identified the genome-wide targets of DBC1 and found that loss of DBC1 inhibits the expression of beta-catenin target genes including PROX1, a transcription factor linked to CRC progression. Mechanistically, DBC1 stabilizes LEF1-beta-catenin interaction by inhibiting SIRT1-mediated beta-catenin deacetylation, thereby enhancing LEF1-beta-catenin complex formation and long-range chromatin looping at the PROX1 locus. Furthermore, DBC1 is also required for the transcriptional activity of PROX1, suggesting that DBC1 has a dual function in regulating beta-catenin-PROX1 signaling axis: as a coactivator for both beta-catenin and PROX1. Importantly, loss of DBC1 inhibited growth and tumorigenic potential of colon cancer cells, and DBC1 expression correlated with shorter relapse-free survival in patients with advanced CRC. Our results firmly establish DBC1 as a critical positive regulator of beta-catenin-PROX1 signaling axis and a key factor in beta-catenin-PROX1-mediated CRC progression.