N-Myc–mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer
Adeline Berger, Nicholas J. Brady, Rohan Bareja, Brian Robinson, Vincenza Conteduca, Michael A. Augello, Loredana Puca, Adnan Ahmed, Etienne Dardenne, Xiaodong Lu, Inah Hwang, Alyssa M. Bagadion, Andrea Sboner, Olivier Elemento, Jihye Paik, Jindan Yu, Christopher E. Barbieri, Noah Dephoure, Himisha Beltran, David S. Rickman
Adeline Berger, Nicholas J. Brady, Rohan Bareja, Brian Robinson, Vincenza Conteduca, Michael A. Augello, Loredana Puca, Adnan Ahmed, Etienne Dardenne, Xiaodong Lu, Inah Hwang, Alyssa M. Bagadion, Andrea Sboner, Olivier Elemento, Jihye Paik, Jindan Yu, Christopher E. Barbieri, Noah Dephoure, Himisha Beltran, David S. Rickman
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Research Article Genetics Oncology

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

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.

Authors

Adeline Berger, Nicholas J. Brady, Rohan Bareja, Brian Robinson, Vincenza Conteduca, Michael A. Augello, Loredana Puca, Adnan Ahmed, Etienne Dardenne, Xiaodong Lu, Inah Hwang, Alyssa M. Bagadion, Andrea Sboner, Olivier Elemento, Jihye Paik, Jindan Yu, Christopher E. Barbieri, Noah Dephoure, Himisha Beltran, David S. Rickman

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Figure 3

N-Myc expression leads to neural lineage gene expression and reduced androgen response.

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N-Myc expression leads to neural lineage gene expression and reduced and...
(A) Experimental schematic with LNCaP-N-Myc or CTL cells and corresponding time points for RNA-seq or ChIP-seq analyses (arrows) in the presence (+A, green) or absence (–A, red) of androgen. (B) Enrichment plots for the Androgen Response and the Neural Stem Cell Differentiation Pathways and Lineage-specific Markers gene sets from indicated conditions. (C) Gene expression (fragments per kilobase of transcript per million mapped reads, FPKM) of AR target genes (left) and neural lineage–associated genes (right) measured by RNA-seq in the indicated cells and conditions, on day 4 (D4, n = 3 biological replicates) and day 42 (D42, n = 2 biological replicates) of androgen withdrawal. *P < 0.05, **P < 0.01, Sidak-Bonferroni–adjusted 2-tailed t test. NS, not significant. (D) Targeted GSEA of RNA-seq data from LNCaP-N-Myc versus CTL cells, without androgen, at D4 or D42 as indicated. *FDR q value < 0.05, **FDR q value < 0.01, ***FDR q value < 0.001. (E) Number of genes differentially expressed (adj. P value < 0.05) in the indicated conditions. ASC, adult stem cell; qNSC, quiescent NSC.