The JNK and Hippo pathways control epithelial integrity and prevent tumor initiation by regulating an overlapping transcriptome

Epithelial organs maintain their integrity and prevent tumor initiation by actively removing defective cells, such as those that have lost apicobasal polarity. Here, we identify how transcription factors of two key signaling pathways—Jun-N-terminal kinase (JNK) and Hippo—regulate epithelial integrity by controlling transcription of an overlapping set of target genes. Targeted DamID experiments reveal that, in proliferating cells of the Drosophila melanogaster eye, the AP-1 transcription factor Jun and the Hippo pathway transcription regulators Yorkie and Scalloped bind to a common suite of target genes that promote organ growth. In defective neoplastic cells, AP-1 transcription factors repress transcription of growth genes together with the C-terminal binding protein (CtBP) co-repressor. If gene repression by AP-1/CtBP fails, neoplastic tumor growth ensues, driven by Yorkie/Scalloped. Thus, AP-1/CtBP eliminates defective cells and prevents tumor initiation by acting in parallel to Yorkie/Scalloped to repress expression of a shared transcriptome. These findings shed new light on the maintenance of epithelial integrity and tumor suppression. [Display omitted] •The JNK pathway acts in parallel to the Hippo pathway to limit neoplastic growth•Hippo and JNK pathway transcription factors bind an overlapping set of target genes•AP-1 and CtBP repress transcription of growth genes in neoplastic epithelial cells•The JNK pathway controls neoplastic, but not normal or hyperplastic, tissue growth Mitchell et al. identify how the transcription factors of the JNK and Hippo pathways regulate epithelial integrity by controlling transcription of an overlapping set of target genes. In cells with disrupted polarity, neoplastic tumor growth is prevented by AP-1 and CtBP-mediated repression of Hippo pathway target genes.