Oncotarget

Research Papers:

Critical role of phosphorylation of serine 165 of YBX1 on the activation of NF-κB in colon cancer

Lakshmi Prabhu, Rasika Mundade, Benlian Wang, Han Wei, Antja-Voy Hartley, Matthew Martin, Kyle McElyea, Constance J. Temm, George Sandusky, Yunlong Liu and Tao Lu _

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Oncotarget. 2015; 6:29396-29412. https://doi.org/10.18632/oncotarget.5120

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Abstract

Lakshmi Prabhu1,*, Rasika Mundade1,*, Benlian Wang2, Han Wei1, Antja-Voy Hartley1, Matthew Martin1, Kyle McElyea3, Constance J. Temm3, George Sandusky3, Yunlong Liu4,5 and Tao Lu1,4,6

1 Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA

2 Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, USA

3 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

4 Department of Medical and Molecular Genetics, Medical Research and Library Building, Indianapolis, IN, USA

5 Center for Computational Biology and Bioinformatics, Health Information and Translational Sciences, Indianapolis, IN, USA

6 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

* These authors have contributed equally to this work

Correspondence to:

Tao Lu, email:

Keywords: colon cancer, NF-κB, phosphorylation, serine, YBX1

Received: December 30, 2014 Accepted: July 24, 2015 Published: August 08, 2015

Abstract

Y-box binding protein 1 [YBX1] is a multifunctional protein known to facilitate many of the hallmarks of cancer. Elevated levels of YBX1 protein are highly correlated with cancer progression, making it an excellent marker in cancer. The connection between YBX1 and the important nuclear factor κB [NF-κB] has never been reported. Here, we show that overexpression of wild type YBX1 [WT-YBX1] activates NF-κB, suggesting that YBX1 is a potential NF-κB activator. Furthermore, using mass spectrometry analysis we identified novel phosphorylation of serine 165 [S165] on YBX1. Overexpression of the S165A-YBX1 mutant in either HEK293 cells or colon cancer HT29 cells showed dramatically reduced NF-κB activating ability as compared with that of WT-YBX1, confirming that S165 phosphorylation is critical for the activation of NF-κB by YBX1. We also show that expression of the S165A-YBX1 mutant dramatically decreased the expression of NF-κB-inducible genes, reduced cell growth, and compromised tumorigenic ability as compared with WT-YBX1. Taken together, we provide the first evidence that YBX1 functions as a tumor promoter via NF-κB activation, and phosphorylation of S165 of YBX1 is critical for this function. Therefore, our important discovery may lead to blocking S165 phosphorylation as a potential therapeutic strategy to treat colon cancer.


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