The <i>CIC-ERF</i> co-deletion underlies fusion-independent activation of ETS family member, ETV1, to drive prostate cancer progression.

Abstract

Human prostate cancer can result from chromosomal rearrangements that lead to aberrant ETS gene expression. The mechanisms that lead to fusion-independent ETS factor upregulation and prostate oncogenesis remain relatively unknown. Here, we show that two neighboring transcription factors, Capicua (<i>CIC</i>) and ETS2 repressor factor (<i>ERF</i>), which are co-deleted in human prostate tumors can drive prostate oncogenesis. Concurrent <i>CIC</i> and <i>ERF</i> loss commonly occur through focal genomic deletions at chromosome 19q13.2. Mechanistically, <i>CIC</i> and <i>ERF</i> co-bind the proximal regulatory element and mutually repress the ETS transcription factor, <i>ETV1</i>. Targeting ETV1 in <i>CIC</i> and <i>ERF</i>-deficient prostate cancer limits tumor growth. Thus, we have uncovered a fusion-independent mode of ETS transcriptional activation defined by concurrent loss of <i>CIC</i> and <i>ERF</i>.