KMT2C Deficiency Drives Luminal Transdifferentiation into Double-Negative Prostate Cancer and Sensitizes to Fatty Acid Synthase Inhibition [RNA-Seq]

Double-negative prostate cancer (DNPC), characterized by AR-null tumors with inherent plasticity, predominantly arises following androgen deprivation therapy (ADT). However, the cellular origin, signaling hierarchy, and treatment strategies for this lethal subtype remain unclear. Here, we demonstrate that the loss of KMT2C, a histone H3K4 methylation transferase preferentially mutated in the DNPC subtype, collaborates with ADT to drive the transformation of luminal tumors into DNPC. Our findings reveal that DNPC arises from the transdifferentiation of luminal cells rather than basal cell expansion. This transdifferentiation is orchestrated by the upregulation of ΔNp63, induced by the dual inactivation of AR and KMT2C. Treatment with antiandrogens facilitates KMT2C binding to the enhancers of a subset of AR-regulated genes, compensating for AR inactivation to preserve the luminal identity. Among these, ARPP2 maintains its expression via KMT2C-dependent enhancer-promoter communication following AR inactivation. mRNA profiles of prostate epithelium (EpCAM+; CD24A+; CD49Flow cells) collected from PtenPC−/− and PtenPC−/− mice with and without ADT; mRNA profiles of the organoids of TP, TPK and TPKP mice treated with ENZ; mRNA profiles of prostate organoids(derived from TPK-Sham & TPK-DNPC mice) with and without TVB2640 treatment.