The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway

TLDR

β‑Catenin links cadherin-mediated adhesion to the cytoskeleton and, when stabilized in colorectal cancer, activates LEF‑1–dependent transcription of largely unknown target genes. The study demonstrates that cyclin D1 is a direct transcriptional target of the β‑catenin/LEF‑1 pathway via a LEF‑1 binding site in its promoter. In colon cancer cells, β‑catenin activation drives cyclin D1 expression, while inhibitors of β‑catenin, APC, axin, or cadherin suppress its promoter activity, indicating that β‑catenin–mediated cyclin D1 up‑regulation promotes uncontrolled cell‑cycle progression.

Abstract

β-Catenin plays a dual role in the cell: one in linking the cytoplasmic side of cadherin-mediated cell–cell contacts to the actin cytoskeleton and an additional role in signaling that involves transactivation in complex with transcription factors of the lymphoid enhancing factor (LEF-1) family. Elevated β-catenin levels in colorectal cancer caused by mutations in β-catenin or by the adenomatous polyposis coli molecule, which regulates β-catenin degradation, result in the binding of β-catenin to LEF-1 and increased transcriptional activation of mostly unknown target genes. Here, we show that the cyclin D1 gene is a direct target for transactivation by the β-catenin/LEF-1 pathway through a LEF-1 binding site in the cyclin D1 promoter. Inhibitors of β-catenin activation, wild-type adenomatous polyposis coli, axin, and the cytoplasmic tail of cadherin suppressed cyclin D1 promoter activity in colon cancer cells. Cyclin D1 protein levels were induced by β-catenin overexpression and reduced in cells overexpressing the cadherin cytoplasmic domain. Increased β-catenin levels may thus promote neoplastic conversion by triggering cyclin D1 gene expression and, consequently, uncontrolled progression into the cell cycle.