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

TitleN-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer.
Publication TypeJournal Article
Year of Publication2019
AuthorsBerger A, Brady NJ, Bareja R, Robinson B, Conteduca V, Augello MA, Puca L, Ahmed A, Dardenne E, Lu X, Hwang I, Bagadion AM, Sboner A, Elemento O, Paik J, Yu J, Barbieri CE, Dephoure N, Beltran H, Rickman DS
JournalJ Clin Invest
Date Published2019 07 01
KeywordsAnimals, Cell Line, Tumor, Cell Lineage, Cell Plasticity, DNA, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, Transgenic, N-Myc Proto-Oncogene Protein, Neoplasm Transplantation, Prostatic Neoplasms, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, Signal Transduction, Transcriptome

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-co-factors (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 EZH2 inhibition to reverse the N-Myc-induced suppression of epithelial lineage genes. Altogether, our data provide insights on 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.

Alternate JournalJ. Clin. Invest.
PubMed ID31260412
PubMed Central IDPMC6715370
Grant ListK08 CA187417 / CA / NCI NIH HHS / United States
R37 CA215040 / CA / NCI NIH HHS / United States
R01 AG048284 / AG / NIA NIH HHS / United States
R01 CA230913 / CA / NCI NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States
T32 CA203702 / CA / NCI NIH HHS / United States