Oncotarget

Research Papers:

Elevated TATA-binding protein expression drives vascular endothelial growth factor expression in colon cancer

Sandra A.S. Johnson, Justin J. Lin, Christopher J. Walkey, Michael P. Leathers, Cristian Coarfa and Deborah L. Johnson _

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Oncotarget. 2017; 8:48832-48845. https://doi.org/10.18632/oncotarget.16384

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Abstract

Sandra A.S. Johnson1, Justin J. Lin2, Christopher J. Walkey1, Michael P. Leathers3, Cristian Coarfa1 and Deborah L. Johnson1

1Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas, United States of America

2Zymo Research, Irvine, California, United States of America

3Department of Orthopedic Surgery, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California, United States of America

Correspondence to:

Deborah L. Johnson, email: Deborah.Johnson@bcm.edu

Keywords: VEGFA, TATA-binding protein, colon cancer, gene expression

Received: February 14, 2017     Accepted: March 13, 2017     Published: March 20, 2017

ABSTRACT

The TATA-binding protein (TBP) plays a central role in eukaryotic gene transcription. Given its key function in transcription initiation, TBP was initially thought to be an invariant protein. However, studies showed that TBP expression is upregulated by oncogenic signaling pathways. Furthermore, depending on the cell type, small increases in cellular TBP amounts can induce changes in cellular growth properties towards a transformed phenotype. Here we sought to identify the specific TBP-regulated gene targets that drive its ability to induce tumorigenesis. Using microarray analysis, our results reveal that increases in cellular TBP concentrations produce selective alterations in gene expression that include an enrichment for genes involved in angiogenesis. Accordingly, we find that TBP levels modulate VEGFA expression, the master regulator of angiogenesis. Increases in cellular TBP amounts induce VEGFA expression and secretion to enhance cell migration and tumor vascularization. TBP mediates changes in VEGFA transcription requiring its recruitment at a hypoxia-insensitive proximal TSS, revealing a mechanism for VEGF regulation under non-stress conditions. The results are clinically relevant as TBP expression is significantly increased in both colon adenocarcinomas as well as adenomas relative to normal tissue. Furthermore, TBP expression is positively correlated with VEGFA expression. Collectively, these studies support the idea that increases in TBP expression contribute to enhanced VEGFA transcription early in colorectal cancer development to drive tumorigenesis.


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