title: Positive regulation of β-catenin-PROX1 signaling axis by DBC1 in colon cancer progression.
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.
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Cancer Center, Seoul, Korea.|Department of Biomedical Sciences, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: E J
authors.initials: EJ
authors.lastname: Yu
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Cancer Center, Seoul, Korea.|Department of Pathology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Cancer Center, Seoul, Korea.|Department of Biomedical Sciences, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Clinical Research, Dongnam Institute of Radiological and Medical Sciences, Busan, Korea.
authors.forename: K
authors.initials: K
authors.lastname: Heo
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Ou
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Stallcup
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Cancer Center, Seoul, Korea.|Department of Biomedical Sciences, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D019073:HT29 Cells; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C527450:CCAR2 protein, human; D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D000098551:Prospero-Related Homeobox 1 Protein