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 5

N-Myc interacts with known AR cofactors to alter DNA binding.

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N-Myc interacts with known AR cofactors to alter DNA binding. (A) Motif ...
(A) Motif analysis of unique N-Myc peaks with or without androgen obtained by ChIP-seq in LNCaP-N-Myc cells. Scores correspond to log2(% target/% background). All motifs shown are enriched with a P value < 10–5 and are listed with their best predicted match to a known protein family. *Percentage background of MEF2A motif was 0% and was subsequently adjusted to 0.001% to calculate a score. (B) Overlap between FOXA1 or HOXB13 ChIP-seq peaks in the LNCaP-N-Myc cells in the presence or absence of androgen on day 4. (C) Comparison of N-Myc binding with AR (GSE69045), FOXA1 (CTL cells: GSE69045) and HOXB13 binding with or without androgen, N-Myc in BE2C neuroblastoma cells (GSE80151), and C-Myc in LNCaP. Numbers represent the percentage of N-Myc peaks in each condition overlapping with the indicated cofactor. (D) Overlap of N-Myc peaks (enriched and unique in –A) with AR, HOXB13, or FOXA1 peaks in the indicated conditions. (E) Distribution of FOXA1 and HOXB13 binding at N-Myc–bound sites ± 4 kb in the indicated conditions. (F) Top: ChIP-seq tracks of genes cobound by N-Myc and FOXA1, independently of AR (in CTL cells), in the indicated conditions. Bottom: Effect of FOXA1 knockdown by siRNA (see Western blot inset) on N-Myc binding assessed by ChIP-qPCR. **P < 0.01 by Sidak-Bonferroni–adjusted 2-tailed t test. (G) Scatter plot of log2(fold change of N-Myc–bound peptides versus IgG-bound peptides, identified by RIME) with (x axis) and without (y axis) androgen (n = 4 biological replicates per condition). Lines correspond to the regression line ± 1.7 Z. com., common; enr., enriched; uni., unique; FC, fold change; NB, neuroblastoma.