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.
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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 6

N-Myc promotes bivalency on neural lineage genes.

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N-Myc promotes bivalency on neural lineage genes. (A) H3K27me3 binding p...
(A) H3K27me3 binding profiles within 8 kb centered at H3K4me3 peaks in LNCaP CTL and N-Myc cells, with and without androgen as specified. (B) Left: Number of H3K4me3, H3K27me3, or H3K4me3/H3K27me3 bivalent peaks in common (com.) or unique to the conditions on day 4 (D4) as indicated. Right: Top 5 gene sets from GSEA for uniquely bivalently marked genes in the absence of androgen from LNCaP-N-Myc cells (red) or CTL cells (black). (C) Left: Number of H3K4me3, H3K27me3, and bivalent peaks also bound by N-Myc with or without androgen. Right: H3K4me3, H3K27me3, and N-Myc binding profiles on bivalent peaks within 8 kb centered at H3K4me3 peaks, in LNCaP-N-Myc cells in the absence of androgen. (D) Examples of N-Myc and histone mark ChIP-seq tracks as indicated. (E) Enrichment plot of the bivalent genes identified in LNCaP-N-Myc –A cells on D4 measured in LNCaP-N-Myc –A cells versus LNCaP-CTL –A cells on D42. (F) Unsupervised clustering of the genes that were bivalent on D4 and differentially expressed (adj. P < 0.05) between LNCaP-N-Myc and LNCaP-CTL cells without androgen on D42.