Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA.
Oncogene. 2010 Mar 25;29(12):1763-72. doi: 10.1038/onc.2009.459. Epub 2009 Dec 21.
Ubc9 is an E2-conjugating enzyme that transfers the activated small ubiquitin-like modifier (SUMO) to protein substrates, and thus it has an important function in sumoylation-mediated cellular pathways. We have earlier reported that Ubc9 promotes tumor growth in the xenograft mouse model using breast cancer cell line MCF-7 in part through regulation of Bcl-2 expression. In this study, we show that ectopic expression of wild-type Ubc9 (Ubc9-WT) promotes cell invasion and metastasis. Surprisingly, the dominant negative mutant Ubc9 (Ubc9-DN) also causes the same phenotype, indicating that the ability of Ubc9 to promote invasion and metastasis is distinct from its ability to conjugate SUMO to protein substrates. Of considerable interest, several microRNAs such as miR-224 are regulated by Ubc9. Although ectopic expression of Ubc9 causes downregulation of miR-224, suppression of Ubc9 by Ubc9-siRNAs leads to its upregulation. We further show that miR-224 can inhibit cell invasion and directly targets CDC42 and CXCR4, and that suppression of CDC42 and CXCR4 by RNAi causes inhibition of Ubc9-mediated invasion. Together, these results show a molecular link between Ubc9 and the metastasis genes such as CDC42 and CXCR4, and thus provide new insight into the mechanism by which Ubc9 promotes tumor invasion and metastasis.
Ubc9 是一种 E2 连接酶，可将激活的小泛素样修饰物（SUMO）转移至蛋白质底物上，因此在 SUMO 介导的细胞途径中具有重要功能。我们之前的研究报告称，Ubc9 通过调节 Bcl-2 表达，在 MCF-7 乳腺癌细胞系的异种移植小鼠模型中促进肿瘤生长。在这项研究中，我们表明，野生型 Ubc9（Ubc9-WT）的异位表达可促进细胞侵袭和转移。令人惊讶的是，显性负突变体 Ubc9（Ubc9-DN）也会导致相同的表型，这表明 Ubc9 促进侵袭和转移的能力与其将 SUMO 缀合至蛋白质底物的能力不同。有趣的是，几种 microRNA，如 miR-224，受 Ubc9 调控。尽管 Ubc9 的异位表达导致 miR-224 下调，但 Ubc9-siRNAs 对 Ubc9 的抑制导致其上调。我们进一步表明，miR-224 可抑制细胞侵袭，并直接靶向 CDC42 和 CXCR4，而 RNAi 对 CDC42 和 CXCR4 的抑制会导致 Ubc9 介导的侵袭受到抑制。总之，这些结果表明 Ubc9 与转移基因（如 CDC42 和 CXCR4）之间存在分子联系，从而为 Ubc9 促进肿瘤侵袭和转移的机制提供了新的见解。
