An Interaction with Ewing’s Sarcoma Breakpoint Protein EWS Defines a Specific Oncogenic Mechanism of ETS Factors Rearranged in Prostate Cancer

Abstract

Summary More than 50% of prostate tumors have a chromosomal rearrangement resulting in aberrant expression of an oncogenic ETS family transcription factor. However, mechanisms that differentiate the function of oncogenic ETS factors expressed in prostate tumors from non-oncogenic ETS factors expressed in normal prostate are unknown. Here we find that four oncogenic ETS, ERG, ETV1, ETV4, and ETV5, and no other ETS, interact with the Ewing’s sarcoma breakpoint protein, EWS. This EWS interaction was necessary and sufficient for oncogenic ETS functions including gene activation, cell migration, clonogenic survival, and transformation. Significantly, the EWS interacting region of ERG has no homology with that of ETV1, ETV4, and ETV5. Therefore this finding may explain how divergent ETS factors have a common oncogenic function. Strikingly, EWS is fused to various ETS factors by the chromosome translocations that cause Ewing’s sarcoma. Therefore, these findings link oncogenic ETS function in both prostate cancer and Ewing’s sarcoma.

Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1 via an R-loop-dependent mechanism

“…Transwell cell migration and clonogenic growth assays were performed in overexpression lines. Expression of flEWS induced significant cell migration and clonogenic growth compared to vector expressing cells, consistent with our previous work (Kedage et al, 2016). Additionally, ctEWS expression promoted these phenotypes to a similar extent as flEWS.…”

“…Both nuclear and cytoplasmic (Andersson et al, 2008), EWS, the protein encoded by EWSR1, has transcription-dependent and transcription-independent roles. We have previously reported that EWS can act as a transcriptional co-activator in prostate cancer (Kedage et al, 2016); other reported nuclear functions of EWS include the regulation of splicing and DNA damage repair (Dutertre et al, 2010;Gorthi et al, 2018;Paronetto et al, 2011). Sedimentation studies suggest that cytoplasmic EWS associates with dense, ribosome-containing fractions as well as lighter fractions that also contain the plasma membrane (Felsch et al, 1999).…”

“…Full length EWS was described previously (Kedage et al, 2016) , the N-terminal EWS isoform was cloned from LNCaP total RNA. The C-terminal EWS isoform was cloned from full length.…”

“…We previously found that EWS plays an important role in prostate cancer (Kedage et al, 2016), therefore we investigated the relationship between EWSR1 expression and AR expression, as AR is essential for prostate cancer development and progression. Using the prostate adenocarcinoma (PRAD) TCGA dataset housed on UCSC Xena Browser (https://xenabrowser.net) (Goldman, 2018), EWSR1 mRNA level was ranked by AR gene expression in 550 patient tumor samples.…”

Molecular genetics of Ewing sarcoma, model systems and finding novel (immuno-) therapeutic targets

“…Additionally, EWSR1-ETS is known to affect epigenetic programs [23,24] , splicing [25,26] , and metabolic activity [27] of EWS. Oncogenic fusions between ETS genes and transcriptional activators are not unique to EWS: in 50%-70% of prostate cancers, similar chromosomal rearrangements are found [28] . The breakpoint position varies, and commonly occurs between exons 7-11 for EWSR1 and exons 4-9 for FLI1, leading to variations in fusion types between patients with EWSR1-FLI1.…”