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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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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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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DOI: https://doi.org/10.1038/onc.2009.81
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