MCC inhibits beta-catenin transcriptional activity by sequestering DBC1 in the cytoplasm

Abstract

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 (bcat) signaling, but the mechanism is poorly understood. Here we show that the b-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 b-cat signaling. RNA interference experiments show that DBC1 promotes b-cat transcriptional activity and that the presence of DBC1 is required for MCC-mediated b-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 b-cat K49 acetylation. Treatment of cells with the SIRT1 inhibitor Nicotinamide reverses MCC-induced deacetylation of b-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 b-cat inhibitory pathway.The mutated in colorectal cancer (MCC) gene was initially discovered because of its proximity to the APC gene on chromosome 5, 1 but its importance as a tumor suppressor gene has only recently been recognized. MCC mutations can drive colon carcinogenesis as shown through an unbiased genetic screen of a mouse model of colorectal cancer. 2 MCC mutations have been found in a wide range of different cancers but in colorectal cancer the MCC gene is most commonly altered through methylation (40-50%), which causes epigenetic silencing of gene expression. 3,4 In liver cancer, MCC expression is lost through LINE-1 retrotransposition events 5 or microRNA targeting. 6 Furthermore, SNPs within the MCC gene and its expression levels are associated with responsiveness to chemotherapy treatment in acute myeloid leukaemia. 7 Limited data are available for other cancer types, except for lung cancer where expression of MCC is also variable but promoter methylation is rare. 8 A number of new biological functions have been identified for MCC, including repression of beta-catenin (b-cat) signaling. 4,[9][10][11] Hyperactivation of the b-cat pathway is widely accepted as a major event in colorectal carcinogenesis, largely due to APC mutation. Mutated APC loses its ability to direct cytoplasmic b-cat for degradation, resulting in nuclear accumulation and inappropriate activation of b-cat-mediated transcription. MCC also inhibits b-cat dependent transcription in vitro, even in the absence of APC, through a mechanism independent and...

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation

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

“…4,19 A recent study demonstrated that DBC1 is required for β-catenin-mediated transcription. 24 However, the detailed mechanism of how DBC1 contributes to β-catenin-mediated transcription has not been fully elucidated. Here we showed several lines of mechanistic evidence that DBC1 promotes β-catenin activity by negatively regulating SIRT1 activity (Figure 3): SIRT1-mediated deacetylation of β-catenin was inhibited by DBC1; DBC1 blocks the interaction of SIRT1 with β-catenin; and SIRT1-mediated repression of β-catenin activity was reversed by DBC1 expression.…”

Therapeutic Inhibition of miR-4260 Suppresses Colorectal Cancer via Targeting MCC and SMAD4

“…Furthermore, function-rescue assays revealed that MCC upregulation was necessary to mediate the suppressive effect of miR-4260 inhibition on cellular proliferation and migration, and resistance to 5-FU treatment in colorectal cancer cells. It has been reported that loss of MCC can lead to the activation of WNT/β-catenin signaling and thus promote cellular proliferation during colorectal tumorogenesis 11, 30, 31. Based on TargetScan bioinformatics analysis (www.targetscan.org), SMAD4 is also predicted to be a target of miR-4260.…”