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
Titre
N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer.
Périodique
The Journal of clinical investigation
Auteur(s)
Berger A., Brady N.J., Bareja R., Robinson B., Conteduca V., Augello M.A., Puca L., Ahmed A., Dardenne E., Lu X., Hwang I., Bagadion A.M., Sboner A., Elemento O., Paik J., Yu J., Barbieri C.E., Dephoure N., Beltran H., Rickman D.S.
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
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
Données d'usage