Oncogenic ETS proteins mimic activated RAS/MAPK signaling in prostate cells
- Peter C. Hollenhorst1,6,
- Mary W. Ferris1,
- Megan A. Hull1,
- Heejoon Chae2,
- Sun Kim2,5 and
- Barbara J. Graves3,4
- 1Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana 47405, USA;
- 2Bioinformatics Program, School of Informatics and Computing, Indiana University, Bloomington, Indiana 47405, USA;
- 3Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA;
- 4Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
Abstract
The aberrant expression of an oncogenic ETS transcription factor is implicated in the progression of the majority of prostate cancers, 40% of melanomas, and most cases of gastrointestinal stromal tumor and Ewing's sarcoma. Chromosomal rearrangements in prostate cancer result in overexpression of any one of four ETS transcription factors. How these four oncogenic ETS genes differ from the numerous other ETS genes expressed in normal prostate and contribute to tumor progression is not understood. We report that these oncogenic ETS proteins, but not other ETS factors, enhance prostate cell migration. Genome-wide binding analysis matched this specific biological function to occupancy of a unique set of genomic sites highlighted by the presence of ETS- and AP-1-binding sequences. ETS/AP-1-binding sequences are prototypical RAS-responsive elements, but oncogenic ETS proteins activated a RAS/MAPK transcriptional program in the absence of MAPK activation. Thus, overexpression of oncogenic ETS proteins can replace RAS/MAPK pathway activation in prostate cells. The genomic description of this ETS/AP-1-regulated, RAS-responsive, gene expression program provides a resource for understanding the role of these ETS factors in both an oncogenic setting and the developmental processes where these genes normally function.
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Footnotes
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↵6 Corresponding author.
E-mail pchollen{at}indiana.edu.
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.17546311.
- Received July 25, 2011.
- Accepted September 12, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press