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

Oncogene volume 35, pages 3410–3418 (2016)Cite this article

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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.

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Acknowledgements

We thank Dr Woo-Young Seo (Sungkyunkwan University) for expert technical assistance and Dr Yong-Kwon Hong (University of Southern California) for providing PROX1 expression and reporter constructs. This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (MISP) (NRF-2013R1A1A2059697 to JHK), National R&D Program through the Dongnam Institute of Radiological and Medical Sciences (DIRAMS) funded by MISP (50590-2015), and the National Institutes of Health (DK043093 to MRS).

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Authors and Affiliations

  1. Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Cancer Center, Seoul, Korea

    E J Yu, S-H Kim, H J Kim & J H Kim

  2. Department of Biomedical Sciences, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea

    E J Yu, H J Kim & J H Kim

  3. Department of Pathology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea

    S-H Kim

  4. Department of Clinical Research, Dongnam Institute of Radiological and Medical Sciences, Busan, Korea

    K Heo

  5. Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA

    C-Y Ou & M R Stallcup

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  1. E J Yu
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Correspondence to M R Stallcup or J H Kim.

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Yu, E., Kim, SH., Kim, H. et al. Positive regulation of β-catenin–PROX1 signaling axis by DBC1 in colon cancer progression. Oncogene 35, 3410–3418 (2016). https://doi.org/10.1038/onc.2015.401

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