Identification of epigenetic regulators cooperating with oncogene yorkie and notch in promoting tumorigenesis and metastasis in drosophila melanogaster

Abstract

Epigenetic regulators are emerging as cooperating factors that promote the activity of oncogenes in tumorigenesis and metastasis. In this study, we screened 19 epigenetic regulators in Polycomb group genes, Trithorax group genes, other related histone modifiers and chromatin remodeling complexes for oncogenic cooperation with known oncogene Yorkie and Notch using Drosophila TARGET system in wing imaginal discs. We identified potential genetic interaction between Snr1 and Yorkie, where Snr1 knockdown significantly promotes Yorkie-induced overgrowth, resulting in complete loss of apico-basal polarity and formation of metastasis. Snr1 potentially balances between Hippo pathway and other proliferation signals, whereas Yorkie over-expression disrupts such balance and causes neoplasia in Snr1 knockdown constructs. On the other hand, Snr1 knockdown inhibited Notch-induced hyperplasia, indicating context-specificity of Snr1 in tumorigenesis. Finally, Caf1 was shown to be essential for both Yorkie- and Notch-driven overgrowth in wing discs. Caf1 knockdown lead to significantly elevated level of wingless and down-regulation of dMyc, antagonizing Yorkie and Notch target gene activation. These results provided new insights into understanding of mechanisms underlying Yorkie- and Notch-driven tumorigenesis, their complex interaction with epigenetic regulators and revealed potential specific therapeutic targets in cancer treatment.