Common ELF1 deletion in prostate cancer bolsters oncogenic ETS function, inhibits senescence and promotes docetaxel resistance.

Justin A. Budka,Mary W. Ferris,Matthew J. Capone,Peter C. Hollenhorst

doi:10.18632/genesandcancer.182

Abstract

ETS family transcription factors play major roles in prostate tumorigenesis with some acting as oncogenes and others as tumor suppressors. ETS factors can compete for binding at some cis-regulatory sequences, but display specific binding at others. Therefore, changes in expression of ETS family members during tumorigenesis can have complex, multimodal effects. Here we show that ELF1 was the most commonly down-regulated ETS factor in primary prostate tumors, and expression decreased further in metastatic disease. Genome-wide mapping in cell lines indicated that ELF1 has two distinct tumor suppressive roles mediated by distinct cis-regulatory sequences. First, ELF1 inhibited cell migration and epithelial-mesenchymal transition by interfering with oncogenic ETS functions at ETS/AP-1 cis-regulatory motifs. Second, ELF1 uniquely targeted and activated genes that promote senescence. Furthermore, knockdown of ELF1 increased docetaxel resistance, indicating that the genomic deletions found in metastatic prostate tumors may promote therapeutic resistance through loss of both RB1 and ELF1

Highlights

More than half of prostate tumors have a chromosomal rearrangement that results in aberrant expression of an ETS transcription factor that is not normally expressed in prostate cells
To better understand the changes that might be occurring within the ETS family during prostate tumorigenesis, we compared the mRNA expression of 498 prostate tumors against 52 normal adjacent samples using the TCGA Prostate Adenocarcinoma dataset (Figure 1A) [http:// cancergenome.nih.gov/.]
We report that ELF1 can have tumor suppressive functions in prostate epithelial cells and that ELF1 levels are negatively correlated with cancer progression within this tissue

Summary

Introduction

More than half of prostate tumors have a chromosomal rearrangement that results in aberrant expression of an ETS transcription factor that is not normally expressed in prostate cells. Other commonly rearranged ETS family members include ETV1, and ETV4 [1, 2]. These ETS factors, when coupled with additional oncogenic mutations, drive prostate tumorigenesis [3,4,5]. There are many other ETS factors expressed in normal prostate epithelia, and some of these can act as tumor suppressors. The tumor suppressive mechanisms of these normally expressed ETS factors and their interplay with oncogenic ETS factors are not well understood

Methods

Results

Conclusion