Psc and Su(z)2 safeguard intestinal stem cell identity and prevent chinmo-dependent tumorigenesis.

Polycomb group (PcG) genes are epigenetic silencers that maintain transcriptional repression of target genes essential for normal development. However, their roles in adult multipotent stem cell lineages remain poorly understood. Here, we show that simultaneous loss of the PRC1 component Psc and its homolog Su(z)2 in intestinal stem cells (ISCs) of the adult Drosophila midgut leads to tumor formation composed of proliferative, undifferentiated cells. Strikingly, these tumor cells do not activate proliferation-associated pathways, including JAK/STAT, Ras/MAPK, and Wnt, nor do they activate Notch or JAK/STAT signaling, which are essential for ISC differentiation. Transcriptomic and chromatin accessibility profiling reveal widespread downregulation of ISC and progenitor cell identity genes and ectopic activation of neural lineage genes. Among these, chinmo is aberrantly upregulated and required for tumor overgrowth. Notably, loss of other PRC1 components does not recapitulate the tumor phenotype, suggesting that the tumor-suppressive role of Psc and Su(z)2 is independent of canonical PRC1 function. Together, our findings uncover a noncanonical, context-specific tumor-suppressive role for Psc and Su(z)2 in preserving ISC identity and restricting lineage deviation.