Human ERG oncoprotein represses LIM domain binding protein-coding gene .

Human TS elated ene, ERG, a master transcription factor, turns oncogenic upon its out-of-context activation in diverse developmental lineages. However, the mechanism underlying its lineage-specific activation of Notch (N), Wnt, or EZH2-three well-characterized oncogenic targets of ERG-remains elusive. We reasoned that deep homology in genetic tool kits might help uncover such elusive cancer mechanisms in . By heterologous gain of human ERG in , here we reveal which codes for a transcriptional coactivator, LIM-domain-binding (LDB) protein, as its novel target. ERG represses via its direct binding and, indirectly, via E(z)-mediated silencing of its promoter. Downregulation of disrupts LIM-HD complex formed between Chip and Tailup (Tup)-a LIM-HD transcription factor-in the developing notum. A consequent activation of N-driven Wg signaling leads to notum-to-wing transdetermination. These fallouts of ERG gain are arrested upon a simultaneous gain of Chip, sequestration of Wg ligand, and, alternatively, loss of signaling or activity. Finally, we show that the human , a homolog of , is repressed in ERG-positive prostate cancer cells. Besides identifying an elusive target of human ERG, our study unravels an underpinning of its lineage-specific carcinogenesis.