A switch in transcription and cell fate governs the onset of an epigenetically-deregulated tumor in <i>Drosophila</i>.

Abstract

Tumor initiation is often linked to a loss of cellular identity. Transcriptional programs determining cellular identity are preserved by epigenetically-acting chromatin factors. Although such regulators are among the most frequently mutated genes in cancer, it is not well understood how an abnormal epigenetic condition contributes to tumor onset. In this work, we investigated the gene signature of tumors caused by disruption of the <i>Drosophila</i> epigenetic regulator, <i>polyhomeotic (ph).</i> In larval tissue <i>ph</i> mutant cells show a shift towards an embryonic-like signature. Using loss- and gain-of-function experiments we uncovered the embryonic transcription factor <i>knirps (kni)</i> as a new oncogene. The oncogenic potential of <i>kni</i> lies in its ability to activate JAK/STAT signaling and block differentiation. Conversely, tumor growth in <i>ph</i> mutant cells can be substantially reduced by overexpressing a differentiation factor. This demonstrates that epigenetically derailed tumor conditions can be reversed when targeting key players in the transcriptional network.