An intrinsic tumor-suppression mechanism mediated by steroid hormone in Drosophila. Drosophila melanogaster

Polycomb group (PcG) proteins are evolutionarily conserved epigenetic regulators that mediate histone modifications and suppress target gene expression, therefore establish and maintain cellular memory during development1-3. Deregulation of PcG genes is associated with various human cancers, but the mechanisms are incompletely understood4. Polyhomeotic (Ph), one of the Drosophila PcG proteins, can act as a tumor suppressor in larval imaginal discs5, 6. Cells mutant for ph overgrow and give rise to neoplastic tumors during larval development6. Here we report an intrinsic tumor-suppression mechanism mediated by the steroid hormone ecdysone in Drosophila. During metamorphosis, ecdysone transforms tumorigenic ph mutant cells into non-tumorigenic cells, thereby suppressing the malignant growth in adult flies. We demonstrate ecdysone exerts its function by inducing the expression of microRNA lethal-7 (let-7), which suppresses its target gene chinmo, to inhibit the tumorigenic growth of ph mutant cells. Furthermore, we show let-7 can also suppress the overgrowth of brain tumors in brain tumor (brat) mutant flies, indicating this intrinsic mechanism is functional in different tissues to suppress neoplastic growth. As let-7 is highly conserved among metazoans, our findings will be relevant for mechanistic studies and therapeutic applications in human cancers. Overall design: Two replicates each of Ph505 tumor tissue was sequenced at 4 weeks, 8 weeks and 14 weeks. During this time it was cultured in adult fly abdomen and piece of it was transplanted once a week to a new host. This data was compared to three control replicates of wild type eye discs from which the tumor originally derives. Additionally tumor tissue from flies that did eclose was analyzed in triplicates to contrast it to larvae stage tumor and wild type tissue