Adler Adam S, Littlepage Laurie E, Lin Meihong, Kawahara Tiara L A, Wong David J, Werb Zena, Chang Howard Y
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
Cancer Res. 2008 Jan 15;68(2):506-15. doi: 10.1158/0008-5472.CAN-07-3060.
CSN5 has been implicated as a candidate oncogene in human breast cancers by genetic linkage with activation of the poor-prognosis, wound response gene expression signature. CSN5 is a subunit of the eight-protein COP9 signalosome, a signaling complex with multiple biochemical activities; the mechanism of CSN5 action in cancer development remains poorly understood. Here, we show that CSN5 isopeptidase activity is essential for breast epithelial transformation and progression. Amplification of CSN5 is required for transformation of primary human breast epithelial cells by defined oncogenes. The transforming effects of CSN5 require CSN subunits for assembly of the full COP9 signalosome and the isopeptidase activity of CSN5, which potentiates the transcriptional activity of MYC. Transgenic inhibition of CSN5 isopeptidase activity blocks breast cancer progression evoked by MYC and RAS in vivo. These results highlight CSN5 isopeptidase activity in breast cancer progression, suggesting it as a therapeutic target in aggressive human breast cancers.
通过与预后不良的伤口反应基因表达特征激活的遗传连锁分析，CSN5被认为是人类乳腺癌中的一个候选癌基因。CSN5是由八个蛋白质组成的COP9信号体的一个亚基，COP9信号体是一个具有多种生化活性的信号复合体；目前对CSN5在癌症发生发展中的作用机制仍知之甚少。在此，我们表明CSN5异肽酶活性对于乳腺上皮细胞的转化和进展至关重要。特定癌基因诱导原代人乳腺上皮细胞发生转化需要CSN5的扩增。CSN5的转化作用需要CSN亚基来组装完整的COP9信号体以及CSN5的异肽酶活性，而CSN5的异肽酶活性可增强MYC的转录活性。在体内，对CSN5异肽酶活性的转基因抑制可阻断由MYC和RAS诱发的乳腺癌进展。这些结果突出了CSN5异肽酶活性在乳腺癌进展中的作用，表明它是侵袭性人类乳腺癌的一个治疗靶点。
