An epigenetically-deregulated tumor state reveals a new role for embryonic transcription factors as cancer drivers

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 aberration of the epigenetic status contributes to tumor onset. In this work, we investigated the transcriptional signature of tumors caused by disruption of the Drosophila epigenetic regulator, polyhomeotic (ph). In larval tissue, ph mutant cells show a shift towards an embryonic-like signature. Using loss- and gain-of-function experiments, we uncovered the embryonic transcription factor knirps (kni) as a new cancer driver. The oncogenic potential of kni lies in its ability to activate JAK/STAT signaling and block differentiation. Conversely, tumor growth in ph mutant cells can be substantially reduced by overexpressing a differentiation factor. This demonstrates that epigenetically derailed tumor conditions can be reversed by induction of differentiation. Transcriptome analysis of ph505-tumors in Drosophila. Mutant clones FRT19A, ph505 generated in eye-antennal imaginal discs.