title: Mucin 1 C-terminal subunit oncoprotein is a target for small-molecule inhibitors.
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.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yongchun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D000595:Amino Acid Sequence; D047310:Apigenin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019281:Dimerization; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018396:Mucin-1; D015513:Oncogene Proteins; D012333:RNA, Messenger; D047310:Apigenin