MCC inhibits beta-catenin transcriptional activity by sequestering DBC1 in the cytoplasm.
The mutated in colorectal cancer (MCC) is a multifunctional gene showing loss of expression in colorectal and liver cancers. MCC mutations can drive colon carcinogenesis in the mouse and in vitro experiments suggest that loss of MCC function promotes cancer through several important cellular pathways. In particular, the MCC protein is known to regulate beta-catenin (β-cat) signaling, but the mechanism is poorly understood. Here we show that the β-cat repressor function of MCC is strongly impaired by the presence of a disease-associated mutation. We also identify deleted in breast cancer 1 (DBC1) as a new MCC interacting partner and regulator of β-cat signaling. RNA interference experiments show that DBC1 promotes β-cat transcriptional activity and that the presence of DBC1 is required for MCC-mediated β-cat repression. In contrast to all other DBC1 interacting partners, MCC does not interact through the DBC1 Leucine Zipper domain but with a glutamic-acid rich region located between the Nudix and EF-hand domains. Furthermore, MCC overexpression relocalizes DBC1 from the nucleus to the cytoplasm and reduces β-cat K49 acetylation. Treatment of cells with the SIRT1 inhibitor Nicotinamide reverses MCC-induced deacetylation of β-cat K49. These data suggest that the cytoplasmic MCC-DBC1 interaction sequesters DBC1 away from the nucleus, thereby removing a brake on DBC1 nuclear targets, such as SIRT1. This study provides new mechanistic insights into the DBC1-MCC axis as a new APC independent β-cat inhibitory pathway.
Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia.
Laurent
L
Pangon
Dessislava
D
Mladenova
Lauren
L
Watkins
Christa
C
Van Kralingen
Nicola
N
Currey
Sam
S
Al-Sohaily
Patrick
P
Lecine
Jean-Paul
JP
Borg
Maija R J
MR
Kohonen-Corish
D000107:Acetylation; D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism* / Q000502:physiology; D000595:Amino Acid Sequence; D001665:Binding Sites; D002467:Cell Nucleus; D015179:Colorectal Neoplasms; D017124:Conserved Sequence; D003593:Cytoplasm / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C527450:CCAR2 protein, human; C495270:CTNNB1 protein, human; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; C067857:MCC protein, human
DBC1; MCC; SIRT1; beta-catenin; colon cancer; tumor suppressor