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


ABSTRACT: Aberrant activation of Wnt/?-catenin pathway contributes to colorectal cancer (CRC) progression. However, little is known about regulatory mechanisms of the ?-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/?-catenin signaling. We identified the genome-wide targets of DBC1 and found that loss of DBC1 inhibits the expression of ?-catenin target genes including PROX1, a transcription factor linked to CRC progression. Mechanistically, DBC1 stabilizes LEF1-?-catenin interaction by inhibiting SIRT1-mediated ?-catenin deacetylation, thereby enhancing LEF1-?-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 ?-catenin-PROX1 signaling axis: as a coactivator for both ?-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 ?-catenin-PROX1 signaling axis and a key factor in ?-catenin-PROX1-mediated CRC progression.

SUBMITTER: Yu EJ 

PROVIDER: S-EPMC5058359 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Yu E J EJ   Kim S-H SH   Kim H J HJ   Heo K K   Ou C-Y CY   Stallcup M R MR   Kim J H JH  

Oncogene 20151019 26


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 ge  ...[more]

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