N-Myc–mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer
Adeline Berger, … , Himisha Beltran, David S. Rickman
Adeline Berger, … , Himisha Beltran, David S. Rickman
Published July 1, 2019
Citation Information: J Clin Invest. 2019;129(9):3924-3940. https://doi.org/10.1172/JCI127961.
View: Text | PDF
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

×

Figure 7

N-Myc–induced bivalent genes are clinically relevant.

Options: View larger image (or click on image) Download as PowerPoint
N-Myc–induced bivalent genes are clinically relevant. (A) Left: Unsuperv...
(A) Left: Unsupervised clustering of PCa (n = 66), CRPC (n = 73), and NEPC (n = 36) patient samples based on the expression level of the 966 bivalent and N-Myc–bound genes in LNCaP-N-Myc cells on day 4 (D4) without androgen. Right: NEPC score for each cluster group. Graph depicts the median value between the 25th and 75th percentiles, with whiskers indicating the range within 1.5 IQR, Student’s unpaired 2-tailed t test. *P < 1 × 10–3, **P < 1 × 10–5, ***P < 1 × 10–10. (B) Targeted GSEA of bivalent-related gene sets in the 5 NEPC samples with the highest (N-Mychi) or lowest (N-Myclo) level of MYCN expression versus PCa (n = 66) patient samples, on the 5 CRPC with the highest level of MYCN expression versus the 5 lowest, and on PM154 cells treated with an EZH2 inhibitor versus vehicle. *FDR q value < 0.05, **FDR q value < 0.01, ***FDR q value < 0.001. (C) Heatmap of log2(fold change) of genes in NEPC (n = 36) versus PCa (n = 66) or NEPC versus CRPC (n = 73) patient samples. Illustrated genes are bivalent and bound by N-Myc in LNCaP-N-Myc cells without androgen at D4. (D) Fold change expression of the indicated genes based on qRT-PCR data (n = 3 technical replicates) in PM154 following EZH2 knockdown (see Western blot inset). ***P < 0.001 by Sidak-Bonferroni–adjusted 2-tailed t test. FC, fold change.