N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer.
Détails
ID Serval
serval:BIB_157F2BC91A3F
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer.
Périodique
The Journal of clinical investigation
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Statut éditorial
Publié
Date de publication
01/07/2019
Peer-reviewed
Oui
Volume
129
Numéro
9
Pages
3924-3940
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
Publication Status: epublish
Publication Status: epublish
Résumé
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.
Mots-clé
Animals, Cell Line, Tumor, Cell Lineage, Cell Plasticity, DNA/chemistry, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, Transgenic, N-Myc Proto-Oncogene Protein/genetics, N-Myc Proto-Oncogene Protein/metabolism, Neoplasm Transplantation, Prostatic Neoplasms/drug therapy, Prostatic Neoplasms/genetics, Prostatic Neoplasms/metabolism, Prostatic Neoplasms, Castration-Resistant/drug therapy, Prostatic Neoplasms, Castration-Resistant/genetics, Prostatic Neoplasms, Castration-Resistant/metabolism, Receptors, Androgen/genetics, Signal Transduction, Transcriptome, Epigenetics, Genetics, Oncology, Prostate cancer
Pubmed
Web of science
Open Access
Oui
Création de la notice
15/07/2020 11:10
Dernière modification de la notice
16/07/2020 9:43