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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

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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 1

Clinical NEPC is associated with neural lineage.

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Clinical NEPC is associated with neural lineage.
(A) Top: Enrichment plo...
(A) Top: Enrichment plots of the Neural Stem Cell Markers and Lee Neural Crest Stem Cell Up gene sets between indicated groups. Bottom: Targeted GSEA in the 5 NEPC samples with the highest (N-Mychi) or lowest (N-Myclo) level of MYCN expression versus PCa (n = 66) patient samples, NEPC N-Mychi versus NEPC N-Myclo, and on the 5 CRPC with the highest level of MYCN expression versus the 5 lowest. *FDR q value < 0.05, **FDR q value < 0.01, ***FDR q value < 0.001. (B) Kaplan-Meier plots of CRPC (n = 57) patients, NEPC (n = 24) patients, or CRPC plus NEPC (n = 81) patients, stratified into 2 categories according to the median value of MYCN mRNA expression. Survival analysis was performed using the Kaplan-Meier estimator (log-rank test). qNSC, quiescent NSC.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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