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The transcriptional induction of PIK3CA in tumor cells is dependent on the oncoprotein Y-box binding protein-1

Oncogene volume 28, pages 2406–2418 (2009)Cite this article

Abstract

PIK3CA, which codes for the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), is implicated as an oncogene. Despite importance of PIK3CA in cancer, little is known about what drives up its expression in tumor cells. We recently characterized the PIK3CA promoter and reported that it is transcriptionally silenced by the tumor suppressor protein p53. In the present study, we demonstrate that PIK3CA can be induced by the oncogenic transcription factor Y-box binding protein-1 (YB-1). Three YB-1-responsive elements were identified on the PIK3CA promoter using chromatin immunoprecipitation and electrophoretic mobility shift assays. Interestingly, silencing YB-1 with siRNA in models of basal-like breast cancer decreased p110α protein levels regardless of whether PIK3CA was wild type, amplified or mutated. This decrease in p110α led to a reduction in PI3K activity and the downstream signaling primarily through p90 ribosomal S6 kinase and S6 ribosomal protein. Disruption in PIK3CA-dependent signaling suppressed cellular invasion correlative with loss of urokinase plasminogen activator (uPA). Similarly, silencing YB-1 suppressed invasion and uPA production however this was reversible through the introduction of constitutively active PIK3CA. In conclusion, YB-1 is the first reported oncogene to induce the expression of PIK3CA through transcriptional control of its promoter.

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References

  • Anjum R, Blenis J . (2008). The RSK family of kinases: emerging roles in cellular signalling. Nat Rev Mol Cell Biol 9: 747–758.

    Article  CAS  PubMed  Google Scholar 

  • Astanehe A, Arenillas D, Wasserman WW, Leung PC, Dunn SE, Davies BR et al. (2008). Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer. J Cell Sci 121: 664–674.

    Article  CAS  PubMed  Google Scholar 

  • Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S et al. (2004). The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3: 772–775.

    CAS  PubMed  Google Scholar 

  • Bader AG, Kang S, Vogt PK . (2006). Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci USA 103: 1475–1479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carriere A, Ray H, Blenis J, Roux PP . (2008). The RSK factors of activating the Ras/MAPK signaling cascade. Front Biosci 13: 4258–4275.

    Article  CAS  PubMed  Google Scholar 

  • Clark DE, Errington TM, Smith JA, Frierson HF, Weber MJ, Lannigan DA . (2005). The serine/threonine protein kinase, p90 ribosomal S6 kinase, is an important regulator of prostate cancer cell proliferation. Cancer Res 65: 3108–3116.

    Article  CAS  PubMed  Google Scholar 

  • Deleeuw RJ, Zettl A, Klinker E, Haralambieva E, Trottier M, Chari R et al. (2007). Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes. Gastroenterology 132: 1902–1911.

    Article  CAS  PubMed  Google Scholar 

  • Didier DK, Schiffenbauer J, Woulfe SL, Zacheis M, Schwartz BD . (1988). Characterization of the cDNA encoding a protein binding to the major histocompatibility complex class II Y box. Proc Natl Acad Sci USA 85: 7322–7326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dunn SE, Torres JV, Oh JS, Cykert DM, Barrett JC . (2001). Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-I depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase. Cancer Res 61: 1367–1374.

    CAS  PubMed  Google Scholar 

  • Finkbeiner MR, Astanehe A, To K, Fotovati A, Davies AH, Zhao Y et al. (2009). Profiling YB-1 target genes uncovers a new mechanism for MET receptor regulation in normal and malignant human mammary cells. Oncogene 28: 1421–1431.

    Article  CAS  PubMed  Google Scholar 

  • Ghoda L, Lin X, Greene WC . (1997). The 90-kDa ribosomal S6 kinase (pp90rsk) phosphorylates the N-terminal regulatory domain of IkappaBalpha and stimulates its degradation in vitro. J Biol Chem 272: 21281–21288.

    Article  CAS  PubMed  Google Scholar 

  • Gold MR, Duronio V, Saxena SP, Schrader JW, Aebersold R . (1994). Multiple cytokines activate phosphatidylinositol 3-kinase in hemopoietic cells: association of the enzyme with various tyrosine-phosphorylated proteins. J Biol Chem 269: 5403–5412.

    CAS  PubMed  Google Scholar 

  • Gupta S, Ramjaun AR, Haiko P, Wang Y, Warne PH, Nicke B et al. (2007). Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell 129: 957–968.

    Article  CAS  PubMed  Google Scholar 

  • Habibi G, Leung S, Law JH, Gelmon K, Masoudi H, Turbin D et al. (2008). Re-defining prognostic factors for breast cancer: YB-1 is a stronger predictor of relapse and disease specific survival than estrogen receptor or HER-2 across all tumor subtypes. Breast Cancer Res 10: R86.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hollestelle A, Elstrodt F, Nagel JH, Kallemeijn WW, Schutte M . (2007). Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines. Mol Cancer Res 5: 195–201.

    Article  CAS  PubMed  Google Scholar 

  • Horn S, Bergholz U, Jucker M, McCubrey JA, Trumper L, Stocking C et al. (2008). Mutations in the catalytic subunit of class IA PI3K confer leukemogenic potential to hematopoietic cells. Oncogene 27: 4096–4106.

    Article  CAS  PubMed  Google Scholar 

  • Hui RC, Gomes AR, Constantinidou D, Costa JR, Karadedou CT, Fernandez de Mattos S et al. (2008). The forkhead transcription factor FOXO3a increases phosphoinositide-3 kinase/Akt activity in drug-resistant leukemic cells through induction of PIK3CA expression. Mol Cell Biol 28: 5886–5898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV et al. (2005). Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res 65: 10992–11000.

    Article  CAS  PubMed  Google Scholar 

  • Manning BD, Cantley LC . (2007). AKT/PKB signaling: navigating downstream. Cell 129: 1261–1274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T et al. (2006). A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10: 515–527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rayet B, Gelinas C . (1999). Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18: 6938–6947.

    Article  CAS  PubMed  Google Scholar 

  • Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J et al. (2007). RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem 282: 14056–14064.

    Article  CAS  PubMed  Google Scholar 

  • Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X et al. (2005). PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65: 2554–2559.

    Article  CAS  PubMed  Google Scholar 

  • Samuels Y, Velculescu VE . (2004). Oncogenic mutations of PIK3CA in human cancers. Cell Cycle 3: 1221–1224.

    Article  CAS  PubMed  Google Scholar 

  • Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science 304: 554.

    Article  CAS  PubMed  Google Scholar 

  • Shadeo A, Lam WL . (2006). Comprehensive copy number profiles of breast cancer cell model genomes. Breast Cancer Res 8: R9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Shayesteh L, Lu Y, Kuo WL, Baldocchi R, Godfrey T, Collins C et al. (1999). PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21: 99–102.

    Article  CAS  PubMed  Google Scholar 

  • She QB, Chandarlapaty S, Ye Q, Lobo J, Haskell KM, Leander KR et al. (2008). Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to akt signaling. PLoS ONE 3: e3065.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sliva D, Rizzo MT, English D . (2002). Phosphatidylinositol 3-kinase and NF-kappaB regulate motility of invasive MDA-MB-231 human breast cancer cells by the secretion of urokinase-type plasminogen activator. J Biol Chem 277: 3150–3157.

    Article  CAS  PubMed  Google Scholar 

  • Smith JA, Poteet-Smith CE, Xu Y, Errington TM, Hecht SM, Lannigan DA . (2005). Identification of the first specific inhibitor of p90 ribosomal S6 kinase (RSK) reveals an unexpected role for RSK in cancer cell proliferation. Cancer Res 65: 1027–1034.

    Article  CAS  PubMed  Google Scholar 

  • Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al. (2001). Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98: 10869–10874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stratford AL, Fry CJ, Desilets C, Davies AH, Cho YY, Li Y et al. (2008). Y-box binding protein-1 (YB-1) serine 102 is a downstream target of p90 ribosomal S6 kinase (RSK) in basal-like breast cancer cells. Breast Cancer Res 10: R99.

    Article  PubMed  PubMed Central  Google Scholar 

  • Stratford AL, Habibi G, Astanehe A, Jiang H, Hu K, Park E et al. (2007). Epidermal growth factor receptor (EGFR) is transcriptionally induced by the Y-box binding protein-1 (YB-1) and can be inhibited with Iressa in basal-like breast cancer, providing a potential target for therapy. Breast Cancer Res 9: R61.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sunters A, Fernandez de Mattos S, Stahl M, Brosens JJ, Zoumpoulidou G, Saunders CA et al. (2003). FoxO3a transcriptional regulation of bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem 278: 49795–49805.

    Article  CAS  PubMed  Google Scholar 

  • Sutherland BW, Kucab J, Wu J, Lee C, Cheang MC, Yorida E et al. (2005). Akt phosphorylates the Y-box binding protein 1 at Ser102 located in the cold shock domain and affects the anchorage-independent growth of breast cancer cells. Oncogene 24: 4281–4292.

    Article  CAS  PubMed  Google Scholar 

  • Ueki K, Fruman DA, Brachmann SM, Tseng YH, Cantley LC, Kahn CR . (2002). Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol Cell Biol 22: 965–977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vanhaesebroeck B, Alessi DR . (2000). The PI3K–PDK1 connection: more than just a road to PKB. Biochem J 346 (Part 3): 561–576.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Woo MM, Salamanca CM, Minor A, Auersperg N . (2007). An improved assay to quantitate the invasiveness of cells in modified Boyden chambers. in vitro Cell Dev Biol Anim 43: 7–9.

    Article  PubMed  Google Scholar 

  • Wu G, Xing M, Mambo E, Huang X, Liu J, Guo Z et al. (2005). Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res 7: R609–R616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu J, Stratford AL, Astanehe A, Dunn SE . (2007). YB-1 is a transcription/translation factor that orchestrates the oncogenome by hardwiring signal transduction to gene expression. Trans Oncogen 2: 49–65.

    CAS  Google Scholar 

  • Wu J, Lee C, Yokom D, Jiang H, Cheang MC, Yorida E et al. (2006). Disruption of the Y-box binding protein-1 results in suppression of the epidermal growth factor receptor and HER-2. Cancer Res 66: 4872–4879.

    Article  CAS  PubMed  Google Scholar 

  • Yehiely F, Moyano JV, Evans JR, Nielsen TO, Cryns VL . (2006). Deconstructing the molecular portrait of basal-like breast cancer. Trends Mol Med 12: 537–544.

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Liu G, Dziubinski M, Yang Z, Ethier SP, Wu G . (2008). Comprehensive analysis of oncogenic effects of PIK3CA mutations in human mammary epithelial cells. Breast Cancer Res Treat 112: 217–227.

    Article  CAS  PubMed  Google Scholar 

  • Zhao JJ, Cheng H, Jia S, Wang L, Gjoerup OV, Mikami A et al. (2006). The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc Natl Acad Sci USA 103: 16296–16300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by the National Cancer Institute of Canada (SED), RO1 CA114017-01A1 (SED and IB), Canadian Institute of Health Research (VD), Canadian Breast Cancer Research Alliance IDEA (WL). AA was supported by the Canadian Institute of Health Research MD/PhD and the Michael Smith Foundation for Health Research Studentships.

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Authors and Affiliations

  1. Departments of Pediatrics and Experimental Medicine, Laboratory for Oncogenomic Research, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada

    A Astanehe, M R Finkbeiner, K To, A Fotovati, A L Stratford & S E Dunn

  2. Department of Medicine, Jack Bell Research Centre, University of British Columbia, Vancouver, British Columbia, Canada

    P Hojabrpour & V Duronio

  3. Department of Cancer Genetics and Developmental Biology, British Columbia Cancer Research Centre, University of British Columbia, Vancouver, British Columbia, Canada

    A Shadeo & W L Lam

  4. Department of Cancer Biology, Wake Forest University, Winston Salem, NC, USA

    I M Berquin

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  1. A Astanehe
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Correspondence to S E Dunn.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Astanehe, A., Finkbeiner, M., Hojabrpour, P. et al. The transcriptional induction of PIK3CA in tumor cells is dependent on the oncoprotein Y-box binding protein-1. Oncogene 28, 2406–2418 (2009). https://doi.org/10.1038/onc.2009.81

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