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DBC1, a master regulator of beta-catenin-PROX1 signaling axis
성균관대학교 융합의과학과 김정훈
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/βcatenin 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 LEF1β-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-PROX1mediated CRC progression.