KDM6 Histone Demethylases Tune Pancreatic Cancer Plasticity

Epigenetic factors often function in a highly context-dependent manner, necessitating rigorous study of their dynamic and complex roles. Here, we uncovered an intricate regulation of tumor development and plasticity by the KDM6 family of H3K27me3 histone demethylases in pancreatic ductal adenocarcinoma (PDAC), a disease with sustained high mortality and limited treatment options.

Temporally resolving KRAS-driven tumor development revealed a switch from tumor suppressive to oncogenic functions for KDM6B, with implications for tumor aggressiveness in rodents and patients. These oncogenic functions were mediated by regulation of NOTCH signaling, a pathway known to promote PDAC tumorigenesis. Concurrent elimination of KDM6A and KDM6B led to profound phenotypic changes resembling sarcomatoid carcinomas, a rare, poorly characterized subtype of human PDAC.