| Literature DB >> 26477307 |
E J Yu1,2, S-H Kim1,3, H J Kim1,2, K Heo4, C-Y Ou5, M R Stallcup5, J H Kim1,2.
Abstract
Aberrant activation of Wnt/β-catenin pathway contributes to colorectal cancer (CRC) progression. However, little is known about regulatory mechanisms of the β-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/β-catenin signaling. We identified the genome-wide targets of DBC1 and found that loss of DBC1 inhibits the expression of β-catenin target genes including PROX1, a transcription factor linked to CRC progression. Mechanistically, DBC1 stabilizes LEF1-β-catenin interaction by inhibiting SIRT1-mediated β-catenin deacetylation, thereby enhancing LEF1-β-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 β-catenin-PROX1 signaling axis: as a coactivator for both β-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 β-catenin-PROX1 signaling axis and a key factor in β-catenin-PROX1-mediated CRC progression.Entities:
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Year: 2015 PMID： 26477307 PMCID： PMC5058359 DOI： 10.1038/onc.2015.401
Source DB: PubMed Journal: Oncogene ISSN： 0950-9232 Impact factor: 9.867