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

被引:63
作者
Astanehe, A. [1 ,2 ]
Finkbeiner, M. R. [1 ,2 ]
Hojabrpour, P. [3 ]
To, K. [1 ,2 ]
Fotovati, A. [1 ,2 ]
Shadeo, A. [4 ]
Stratford, A. L. [1 ,2 ]
Lam, W. L. [4 ]
Berquin, I. M. [5 ]
Duronio, V. [3 ]
Dunn, S. E. [1 ,2 ]
机构
[1] Univ British Columbia, Lab Oncogen Res, Dept Pediat, Child & Family Res Inst, Vancouver, BC V5Z 4H4, Canada
[2] Univ British Columbia, Dept Expt Med, Child & Family Res Inst, Vancouver, BC V5Z 4H4, Canada
[3] Univ British Columbia, Dept Med, Jack Bell Res Ctr, Vancouver, BC V5Z 4H4, Canada
[4] Univ British Columbia, Dept Canc Genet & Dev Biol, British Columbia Canc Res Ctr, Vancouver, BC V5Z 4H4, Canada
[5] Wake Forest Univ, Dept Canc Biol, Winston Salem, NC 27109 USA
关键词
breast cancer; invasion; PI3K; PIK3CA; uPA; YB-1; RIBOSOMAL S6 KINASE; BREAST-CANCER CELLS; MAMMARY EPITHELIAL-CELLS; GROWTH-FACTOR RECEPTOR; PHOSPHATIDYLINOSITOL; 3-KINASE; PLASMINOGEN-ACTIVATOR; HEMATOPOIETIC-CELLS; OVARIAN-CANCER; HIGH-FREQUENCY; COPY NUMBER;
D O I
10.1038/onc.2009.81
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
PIK3CA, which codes for the p110 alpha 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 p110 alpha protein levels regardless of whether PIK3CA was wild type, amplified or mutated. This decrease in p110 alpha 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. Oncogene (2009) 28, 2406-2418; doi:10.1038/onc.2009.81; published online 11 May 2009
引用
收藏
页码:2406 / 2418
页数:13
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