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 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 oncogene. 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 when targeting key players in the transcriptional network.
Highlights
During development, epigenetic regulators are responsible for controlling and restraining cellular plasticity
Loss of an epigenetic regulator leads to acquisition of an embryonic and oncogenic gene signature
With the analysis of a ph mutant transcriptome we highlight the complexity of disrupting global gene expression programs and, with that, newly established transcriptional dependencies
Summary
Epigenetic regulators are responsible for controlling and restraining cellular plasticity. Torres et al found that the protein encoded by knirps activates a signaling pathway that keeps tumor cells unspecialized by blocking their normal progress to a more mature and specialized state – a process known as differentiation. Raising the levels of a different molecule that promotes differentiation caused the tumor cells to grow less These findings suggest that tumors caused when epigenetic regulation goes awry may be reversed by targeting key genes such as knirps. Epigenetic regulators involved in preserving cellular identity are composed of two classes of chromatin proteins, the Polycomb (PcG) and the Trithorax group (TrxG), whose complementary functions maintain the repressed and active gene expression state, respectively (Geisler and Paro, 2015). We found that overexpressing a pro-neural TF leads to reduction of proliferation and suppression of the tumor phenotype
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
