Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is a tumor suppressor and transcription regulator. Menin interacts with various proteins as a scaffold protein and is proposed to play important roles in multiple physiological and pathological processes by controlling gene expression, proliferation, and apoptosis. The mechanisms underlying menin's suppression of tumorigenesis are largely elusive. In this study, we showed that menin was essential for the regulation of canonical Wnt/beta-catenin signaling in cultured cells. The C-terminal domain of menin was able to directly interact with and promote ubiquitin-mediated degradation of beta-catenin. We further revealed that overexpression of menin down-regulated the transcriptional activity of beta-catenin and target gene expression. Moreover, menin efficiently inhibited beta-catenin protein levels, transcriptional activity, and proliferation of human renal carcinoma cells with an activated beta-catenin pathway. Taken together, our results provide novel molecular insights into the tumor suppressor activity of menin, which is partly mediated by proteasomal degradation of beta-catenin and inhibition of Wnt/beta-catenin signaling.