N-Myc–mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer

TLDR

Prostate cancer remains a leading cause of cancer‑related death, and a subset of castration‑resistant tumors acquires androgen‑receptor‑independent neuroendocrine features through lineage plasticity driven in part by aberrant N‑Myc expression, though the underlying mechanisms are not yet understood. Integrative transcriptomic, cistromic, and interactomic profiling of N‑Myc in in‑vivo, in‑vitro, and patient‑derived organoid models revealed a neural lineage switch driven by epigenetic reprogramming. N‑Myc co‑occupies neural‑lineage loci with AR cofactors independently of AR, reprograms lineage‑specific histone marks, and its transcriptional signature accurately classifies advanced prostate cancer patients, while EZH2 inhibition can restore epithelial gene expression, offering a potential therapeutic avenue and predictive biomarker for disease evolution.

Abstract

Despite recent therapeutic advances, prostate cancer remains a leading cause of cancer-related death. A subset of castration-resistant prostate cancers become androgen receptor (AR) signaling independent and develop neuroendocrine prostate cancer (NEPC) features through lineage plasticity. These NEPC tumors, associated with aggressive disease and poor prognosis, are driven, in part, by aberrant expression of N-Myc, through mechanisms that remain unclear. Integrative analysis of the N-Myc transcriptome, cistrome, and interactome using in vivo, in vitro, and ex vivo models (including patient-derived organoids) identified a lineage switch towards a neural identity associated with epigenetic reprogramming. N-Myc and known AR cofactors (e.g., FOXA1 and HOXB13) overlapped, independently of AR, at genomic loci implicated in neural lineage specification. Moreover, histone marks specifically associated with lineage-defining genes were reprogrammed by N-Myc. We also demonstrated that the N-Myc–induced molecular program accurately classifies our cohort of patients with advanced prostate cancer. Finally, we revealed the potential for enhancer of zeste homolog 2 (EZH2) inhibition to reverse the N-Myc–induced suppression of epithelial lineage genes. Altogether, our data provide insights into how N-Myc regulates lineage plasticity and epigenetic reprogramming associated with lineage specification. The N-Myc signature we defined could also help predict the evolution of prostate cancer and thus better guide the choice of future therapeutic strategies.