E3 Ubiquitin Ligases as Molecular Targets in Human Oral Cancers
E3 Ubiquitin Ligases as Molecular Targets in Human Oral Cancers
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DOI：
10.2174/1568009616666151112122336
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发表时间：
2016-01-01
影响因子：
3
通讯作者：
Kitagawa, Masatoshi
中科院分区：
文献类型：
--
作者：
Masumoto, Kazuma;Kitagawa, Masatoshi
泛素-蛋白酶体途径参与多种生物过程。几种致癌 E3 连接酶以肿瘤抑制蛋白为目标，进行泛素介导的降解。或者，一些其他 E3 连接酶充当专门针对癌基因产物的肿瘤抑制因子。这些 E3 连接酶的失调会导致致癌信号和肿瘤抑制途径之间的不平衡，并导致各种人类恶性肿瘤（包括口腔癌、头颈癌）中的细胞转化、肿瘤生长和转移。在口腔癌和头颈癌中观察到细胞周期蛋白依赖性激酶 (CDK) 抑制剂 p27(Kip1) 的促进降解，并且与它们的不良预后相关。 SCFSkp2、KPC 复合体、Pirh2 和 CRL4(DDB2-Artemis) 已被报道为靶向 p27(Kip1) 进行降解的 E3 连接酶。据报道，在口腔癌中，Skp2 和 Pirh2 的过度表达与不良预后相关。因此，针对这些 E3 连接酶的化学抑制剂适用于口腔癌治疗。一些抑制 SCFSkp2 E3 连接酶活性的潜在化合物已被报道。此外，HECT型E3连接酶WWP家族和Smurf1也参与人类口腔癌的发生和生长。因此，针对HECT型E3连接酶的小分子抑制剂被讨论为抗口腔癌药物。
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. SCFSkp2, 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 SCFSkp2 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.