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

COP1 in prostate cancer Translocations in transcription factors in the E26 transformation-specific (ETS) family are common in prostate cancer. Dixit and colleagues now find that the ubiquitin ligase COP1 normally ubiquitinates certain ETS factors, leading to their degradation. The proteins encoded by the translocations, however, lack the COP1 signal and thus evade degradation. COP1 acts as a tumour suppressor, and its deletion causes neoplasias in the mouse prostate by increasing ETS factor levels. The authors also show that the loss of COP1, like ETS translocations, can lead to upregulation of ETS factors in human prostate cancers. 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 1 , 2 , 3 , 4 . 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.