Abstract

Mucin 1 (MUC1) is a heterodimeric protein that is overexpressed in diverse human carcinomas. The oncogenic function of the MUC1 C-terminal subunit (MUC1-C) subunit is dependent on the formation of dimers through its cytoplasmic domain; however, it is not known whether MUC1-C can be targeted with small-molecule inhibitors. In the present work, an assay using the MUC1-C cytoplasmic domain (MUC1-CD) was established to screen small-molecule libraries for compounds that block its dimerization. Using this approach, the flavone apigenin was identified as an inhibitor of MUC1-CD dimerization in vitro and in cells. By contrast, the structurally related flavone baicalein was ineffective in blocking the formation of MUC1-CD dimers. In concert with these results, apigenin, and not baicalein, blocked the localization of MUC1-C to the nucleus. MUC1-C activates MUC1 gene expression in an autoinductive loop, and apigenin, but not baicalein, treatment was associated with down-regulation of MUC1 mRNA levels and MUC1-C protein. The results also demonstrate that apigenin-induced suppression of MUC1-C expression is associated with apoptotic cell death and loss of clonogenic survival. These findings represent the first demonstration that the MUC1-C cytoplasmic domain is a target for the development of small-molecule inhibitors.