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

GSE267773 Mus musculus Genome binding/occupancy profiling by high throughput sequencing; Expression profiling by high throughput sequencing 8 samples Submitted 2025/02/27 Platform GPL24247
Summary
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.
Published in
KMT2C deficiency drives transdifferentiation of double-negative prostate cancer and confer resistance to AR-targeted therapy
Guo J, Li N, Liu Q et al. · Cancer cell 2025 · PMID 40280125 · doi:10.1016/j.ccell.2025.04.002
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Also filed as BioProject PRJNA1112844 and SRA study SRP508441. Searching any of these in the dataset finder brings you back here.

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