COP1 is a tumour suppressor that causes degradation of ETS transcription factors

Abstract

The proto-oncogenes ETV1, ETV4 and ETV5 encode transcription factors in the E26 transformation-specific (ETS) family, which includes the most frequently rearranged and overexpressed genes in prostate cancer. Despite being critical regulators of development, little is known about their post-translational regulation. Here we identify the ubiquitin ligase COP1 (also known as RFWD2) as a tumour suppressor that negatively regulates ETV1, ETV4 and ETV5. ETV1, which is mutated in prostate cancer more often, was degraded after being ubiquitinated by COP1. Truncated ETV1 encoded by prostate cancer translocation TMPRSS2:ETV1 lacks the critical COP1 binding motifs and was 50-fold more stable than wild-type ETV1. Almost all patient translocations render ETV1 insensitive to COP1, implying that this confers a selective advantage to prostate epithelial cells. Indeed, COP1 deficiency in mouse prostate elevated ETV1 and produced increased cell proliferation, hyperplasia, and early prostate intraepithelial neoplasia. Combined loss of COP1 and PTEN enhanced the invasiveness of mouse prostate adenocarcinomas. Finally, rare human prostate cancer samples showed hemizygous loss of the COP1 gene, loss of COP1 protein, and elevated ETV1 protein while lacking a translocation event. These findings identify COP1 as a tumour suppressor whose downregulation promotes prostatic epithelial cell proliferation and tumorigenesis.

ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

“…Given the principal role of Ras signaling in metastases, combined with the fact that Ras signaling is generally refractory to conventional therapy (64,65), targeting ETV4 in prostate cancer may provide an alternative means of inhibiting metastasis. This idea is supported by the potential to target the ubiquitin ligase COP1, which has been shown to regulate ETV function in prostate cancer (66). Thus, our findings support the idea of targeting ETV4 as a means of abrogating Ras signaling in advanced prostate cancer.…”

Proteasomal Degradation of the EWS-FLI1 Fusion Protein Is Regulated by a Single Lysine Residue

“…Most interestingly, EWS-FLI1 displays a higher turnover compared with its full-length proteins EWSR1 and FLI1. In contrast, the ETS proteins ERG and ETV1, which are fused to the TMPRSS2 promoter in prostate cancer, stabilize the protein and confer a physiological advantage to cancer cells (33,34,36). The truncated protein versions display increased stability due to loss of the N-terminal E3 ligase motif.…”

“…If the turnover and subsequent E3 ligase binding of ETS members are conserved, EWS-FLI1 might possibly interact with E3 ligases via its EWSR1 domain, giving rise to a new regulatory mechanism. However, the basic concept that truncated oncogenic TFs are more stable than their wild type counterparts (36) might not apply for fusion proteins consisting of two unrelated protein domains. Whether this is indeed a general paradigm or rather specific for EWSR1-related fusion proteins needs to be further elucidated.…”

“…Considering their high conservation, proteasomal degradation is likely to be the main mechanism of turnover for most ETS family members. Most interestingly, truncated ERG and ETV1 lack the N-terminal E3 binding domain, which results in a delayed turnover of aberrant ETS proteins (34,36). Here, we focus specifically on the turnover of the fusion protein EWS-FLI1, which only harbors the ETS and the C-terminal domain from FLI1.…”

“…Several ETS proteins can be polyubiquitinated by different E3 ligases and subsequently degraded by the proteasome (33)(34)(35)(36). Considering their high conservation, proteasomal degradation is likely to be the main mechanism of turnover for most ETS family members.…”