期刊
ONCOGENE
卷 31, 期 39, 页码 4266-4278出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.599
关键词
KIAA1524; breast cancer; gene expression profile; PLAUR; SERPINE2; PP2A B-subunit
资金
- Academy of Finland [125826, 1131449, 8217676]
- Sigrid Juselius Foundation
- Cancer Society of Finland
- Helsinki University Central Hospital [TYH2009304]
- Foundation of Finnish Cancer Institute
- Cancer Foundation Finland sr [120084, 120139, 110134, 110071] Funding Source: researchfish
- Academy of Finland (AKA) [120139, 120139] Funding Source: Academy of Finland (AKA)
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. Oncogene (2012) 31, 4266-4278; doi:10.1038/onc.2011.599; published online 16 January 2012
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