The Fra3B locus on chromosome 3p14.2 targeting the fragile
histidine triad (Fhit) gene represents one of the most common fragile sites of the human genome and is associated with early preneoplastic and malignant disorders in multiple human
tumors. Fhit was classified as a
tumor suppressor; however, the molecular mechanisms of its function are not well established. Here, we report that Fhit associates with the
lymphoid enhancer-binding factor 1/
T cell factor/
beta-catenin complex by directly binding to
beta-catenin, a major player in the canonical Wnt pathway that is deregulated in numerous forms of human
cancer. In binding to the
beta-catenin C-terminal domain, Fhit represses transcription of target genes such as
cyclin D1, axin2, MMP-14, and
survivin. Knockdown of Fhit reversed this effect, whereas this reversal was not detectable when
beta-catenin was knocked down simultaneously. The Fhit enzymatic activity as a
diadenosine-polyphosphate hydrolase is not required for the down-regulation of
beta-catenin-mediated transcription as examined with an enzymatic inactive Fhit-H96N
protein. ChIPs revealed recruitment of Fhit/
beta-catenin complexes to target gene promoters. In soft
agar assays Fhit and
beta-catenin are involved in regulation of anchorage-independent growth. These observations assign to the
tumor suppressor Fhit an unexpected role in the regulation of
beta-catenin-mediated gene transcription.