NEW YORK (GenomeWeb) – The molecular mechanisms involved in prostate cancer and Ewing's sarcoma appear to be similar, according to researchers from Indiana University.
More than 100,000 men are diagnosed in the US each year with prostate cancer, and about half of prostate cancers harbor a chromosomal rearrangement that causes aberrant expression of an ETS family transcription factor. There are more than two dozen members of the ETS family, but only four have this oncogenic capability: ERG, ETV1, ETV4, and ETV5. Rearrangements most commonly involve ERG.
At the same time, Ewing's sarcoma, a bone and soft tissue cancer that afflicts children and young adults, is caused by a fusion of one of five ETS genes and the EWS gene.
Through a series of studies that they described this week in Cell Reports, Indiana's Peter Hollenhorst and his colleagues have now found that the EWS protein interacts with the four ETS proteins involved in prostate cancer, suggesting a link between the diseases.
"This research shows that the molecular mechanism involved in the development of most prostate cancers is very similar to the molecular mechanism known to cause Ewing's sarcoma," Hollenhorst said in a statement. "It also suggests that this mechanism might be used to explore a common treatment for both diseases, one of which is not often pursued by drug companies due to its rarity."
Through an immunoblot, Hollenhorst and his colleagues found that EWS outside the context of Ewing's sarcoma would interact with four ETS proteins: ERG, ETV1, ETV4, and ETV5, the four that are linked to prostate cancer. Then, in two cancer cell lines, the researchers found that the oncogenic ETS proteins also interacted with EWS. Further, they noted it appeared to be a direct protein interaction.
The researchers fused other, typically non-oncogenic ETS proteins with EWS and gauged their oncogenic ability. Through this, they found that the EWS fusion was enough to enable non-oncogenic ETS proteins to act like the oncogenic ERG protein.
Hollenhorst and his colleagues also traced the region of ERG that interacts with EWS back to ERG P436, and examined the function of wild-type ERG and ERG with a mutation at that EWS interaction site. They found that wild-type ERG promoted cell migration while the mutant form inhibited it. It had a similar effect on clonogenic growth. In addition, in a xenograft model, the researchers found that this interaction with EWS is required for ERG's oncogenic functions.
Through ChIP-seq, Hollenhorst and his colleagues identified six ERG target sites, and analyzed the occupancy of those sites in a prostate cell line when either ERG or ERG with a mutation at its EWS interaction site were expressed. When the mutant ERG was expressed, the researchers noted a decline in EWS occupancy, a pattern they said extended genome-wide. This, they added, indicates that the ERG mutation doesn't affect ERG occupancy, but rather the recruitment of EWS.
They further noted from a transcriptome-level study of ERG, mutant ERG, and shRNA knockdown of ERG in a cell line that EWS acts as a co-activator for a number of ERG target genes.
In previous work, the researchers had found that oncogenic ETS proteins activate gene expression by binding regulatory regions made up of neighboring ETS and AP-1 transcription factor binding sites, sites that are located near cell migration genes. Meanwhile, they said that in Ewing’s sarcoma, EWS-FLI1 activates transcription through regulatory elements that contain GGAA repeats, which is the core ETS binding sequence.
They noted that the repeats haven't been found to be targets of oncogenic ETS in prostate cancer. But when they searched sequences bound by ERG and EWS in a prostate cancer cell line, they found the GGAA repeats. This and other data suggests that oncogenic ETS and EWS bind both ETS/AP-1 sequences and GGAA repeats in prostate cells to activate the transcription of target genes, the researchers said, indicating a common molecular mechanism.
According to Indiana University, Hollenhorst and his colleagues have recently been awarded a grant to screen for molecules that could disrupt these ETSEWS interactions.