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