Calypso, a PcG Gene, Regulates the Development of Tumor-Like Malformation of Eyes via Insulin Signaling Pathway in Drosophila melanogaster

Background. BRCA1-associated protein-1 (BAP1), which is an epigenetic factor, plays an important role in regulating gene expression. BAP1 germline mutation is related to and plays different roles in a variety of human tumorigenesis. Calypso is a homologous gene of BAP1 in Drosophila melanogaster. The physiological and genetic role of Calypso in ocular development during metamorphosis was still less studied. Methods and Results. In this work, we found that the knockdown of calypso in D. melanogaster eyes causes a tumor-like malformation. We first dissected the eye imaginal discs of D. melanogaster and then conducted RNA sequencing analysis, which showed that calypso knockdown could affect the activity of the insulin signaling pathway. Both the expression of insulin signaling pathway reporter genes and the Akt phosphorylation level revealed that insulin signaling pathway had been intensively activated in the eyes of D. melanogaster by calypso knockdown. We further knocked down certain target genes in insulin signaling pathway in the eyes of D. melanogaster whose calypso had been already knocked down, and found that the akt, rheb, s6k, or upd3 knockdown could rescue tumor-like phenotype to different degrees. Among them, the eyes of the D. melanogaster with akt or rheb knockdown were restored to their normal shape. Conclusion. The results suggested that the tumor-like phenotype caused by calypso knockdown in D. melanogaster eyes can be mediated by the hyperactivation of PI3K/Akt/mTOR pathway downstream insulin signaling pathway.