KMT2C Deficiency Drives Luminal Transdifferentiation into Double-Negative Prostate Cancer and Sensitizes to Fatty Acid Synthase Inhibition [ATAC-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. Consequently, KMT2C inactivation reduces ARPP2 expression, leading to p65-dependent upregulation of ΔNp63 and subsequent DNPC development. In our DNPC model, we identified a selective reinstatement of fatty acid synthesis, facilitated by the ΔNp63-dependent SREBP1 transcriptome. This sustains DNPC growth through intensified HRAS palmitoylation and activation of the RAS-MAPK signaling pathway. Our findings underscore the role of KMT2C as an epigenetic checkpoint in restraining DNPC transdifferentiation. This highlights an elevated risk for KMT2C-mutated patients receiving ADT and underscores the potential therapeutic targeting of fatty acid synthesis against DNPC.