title: E3 Ubiquitin Ligases as Molecular Targets in Human Oral Cancers.
abstract: The ubiquitin-proteasome pathway is involved in various biological processes. Several oncogenic E3 ligases target tumor suppressor proteins for ubiquitin-mediated degradation. Alternatively, some other E3 ligases play as a tumor suppressor specifically targeting oncogene products. Deregulation of these E3 ligases induces unbalance between oncogenic signal and tumor suppressor pathway and leads to cellular transformation, tumor growth and metastasis in various human malignancies including oral, and head and neck cancers. Facilitated degradation of the cyclin-dependent kinase (CDK) inhibitor p27(Kip1) has been observed in oral, and head and neck cancers, and is correlated with their poor prognosis. SCF(Skp2), KPC complex, Pirh2 and CRL4(DDB2-Artemis) have been reported as E3 ligases targeting p27(Kip1) for degradation. In oral cancers, it is reported that overexpression of Skp2 and Pirh2 is associated with poor prognosis. Thus, chemical inhibitors against these E3 ligases are applicable for oral cancer therapy. Some potential compounds that inhibit E3 ligase activity of SCF(Skp2) have been reported. Moreover, the HECT-type E3 ligase WWP family and Smurf1 are also involved in the development and growth of human oral cancers. Therefore, small molecule inhibitors against HECT-type E3 ligases are discussed as anti-oral cancer drugs.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan. kazusan@hama-med.ac.jp.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Masumoto
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kitagawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D058990:Molecular Targeted Therapy; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; C436291:CDKN1B protein, human; D004791:Enzyme Inhibitors; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C498342:SMURF1 protein, human; C471642:WWP1 protein, human; C465283:WWP2 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex