Turku Centre for Biotechnology, Turku Graduate School of Biomedical Sciences, Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
Oncogene. 2012 Sep 27;31(39):4266-78. doi: 10.1038/onc.2011.599. Epub 2012 Jan 16.
Protein phosphatase 2A (PP2A) is a critical human tumor-suppressor complex. A recently characterized PP2A inhibitor protein, namely cancerous inhibitor of PP2A (CIP2A), has been found to be overexpressed at a high frequency in most of the human cancer types. However, our understanding of gene expression programs regulated by CIP2A is almost absent. Moreover, clinical relevance of the CIP2A-regulated transcriptome has not been addressed thus far. Here, we report a high-confidence transcriptional signature regulated by CIP2A. Bioinformatic pathway analysis of the CIP2A signature revealed that CIP2A regulates several MYC-dependent and MYC-independent gene programs. With regard to MYC-independent signaling, JNK2 expression and transwell migration were inhibited by CIP2A depletion, whereas MYC depletion did not affect either of these phenotypes. Instead, depletion of either CIP2A or MYC inhibited cancer cell colony growth with statistically indistinguishable efficiency. Moreover, CIP2A depletion was shown to regulate the expression of several established MYC target genes, out of which most were MYC-repressed genes. CIP2A small-interfering RNA-elicited inhibition of colony growth or activation of MYC-repressed genes was reversed at large by concomitant PP2A inhibition. Finally, the CIP2A signature was shown to cluster with basal-type and human epidermal growth factor receptor (HER)2-positive (HER2+) breast cancer signatures. Accordingly, CIP2A protein expression was significantly associated with basal-like (P=0.0014) and HER2+ (P<0.0001) breast cancers. CIP2A expression also associated with MYC gene amplification (P<0.001). Taken together, identification of CIP2A-driven transcriptional signature, and especially novel MYC-independent signaling programs regulated by CIP2A, provides important resource for understanding CIP2A's role as a clinically relevant human oncoprotein. With regard to MYC, these results both validate CIP2A's role in regulating MYC-mediated gene expression and provide a plausible novel explanation for the high MYC activity in basal-like and HER2+ breast cancers.
蛋白磷酸酶 2A（PP2A）是一种关键的人类肿瘤抑制复合物。最近鉴定的一种 PP2A 抑制剂蛋白，即癌性 PP2A 抑制剂（CIP2A），在大多数人类癌症类型中高频率过表达。然而，我们对 CIP2A 调节的基因表达程序几乎没有了解。此外，迄今为止尚未解决 CIP2A 调节的转录组的临床相关性。在这里，我们报告了一个由 CIP2A 调节的高可信度转录特征。CIP2A 特征的生物信息途径分析表明，CIP2A 调节几个 MYC 依赖性和 MYC 非依赖性基因程序。就 MYC 非依赖性信号而言，CIP2A 耗竭抑制 JNK2 表达和 Transwell 迁移，而 MYC 耗竭不影响这两种表型中的任何一种。相反，CIP2A 或 MYC 的耗竭以统计学上无差异的效率抑制癌细胞集落生长。此外，已经表明 CIP2A 耗竭调节几个已建立的 MYC 靶基因的表达，其中大多数是 MYC 抑制基因。CIP2A 小干扰 RNA 引发的集落生长抑制或 MYC 抑制基因的激活，通过同时抑制 PP2A 可得到很大逆转。最后，CIP2A 特征与基底型和人表皮生长因子受体（HER）2 阳性（HER2+）乳腺癌特征聚类。因此，CIP2A 蛋白表达与基底样（P=0.0014）和 HER2+（P<0.0001）乳腺癌显著相关。CIP2A 表达也与 MYC 基因扩增相关（P<0.001）。总之，鉴定 CIP2A 驱动的转录特征，特别是 CIP2A 调节的新型 MYC 非依赖性信号程序，为理解 CIP2A 作为一种具有临床相关性的人类癌蛋白的作用提供了重要资源。就 MYC 而言，这些结果既验证了 CIP2A 在调节 MYC 介导的基因表达中的作用，又为基底样和 HER2+乳腺癌中高 MYC 活性提供了一种合理的新解释。
