Human ERG oncoprotein represses <i>a Drosophila</i> LIM domain binding protein-coding gene <i>Chip</i>.

Abstract

Human <u>E</u>TS <u>R</u>elated <u>G</u>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 <i>Drosophila</i>. By heterologous gain of human ERG in <i>Drosophila</i>, here we reveal <i>Chip,</i> which codes for a transcriptional coactivator, LIM-domain-binding (LDB) protein, as its novel target. ERG represses <i>Drosophila Chip</i> via its direct binding and, indirectly, via E(z)-mediated silencing of its promoter. Downregulation of <i>Chip</i> 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 <i>N</i> signaling or <i>E(z)</i> activity. Finally, we show that the human <i>LDB1</i>, a homolog of <i>Drosophila Chip</i>, 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.