N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer.
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
Neoplasm Transplantation
Prostatic Neoplasms
/ drug therapy
Prostatic Neoplasms, Castration-Resistant
/ drug therapy
Receptors, Androgen
/ genetics
Signal Transduction
Transcriptome
Epigenetics
Genetics
Oncology
Prostate cancer
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
01 07 2019
01 07 2019
Historique:
entrez:
2
7
2019
pubmed:
2
7
2019
medline:
24
6
2020
Statut:
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.
Identifiants
pubmed: 31260412
pii: 127961
doi: 10.1172/JCI127961
pmc: PMC6715370
doi:
pii:
Substances chimiques
MYCN protein, human
0
N-Myc Proto-Oncogene Protein
0
Receptors, Androgen
0
DNA
9007-49-2
Types de publication
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.
Langues
eng
Sous-ensembles de citation
IM
Pagination
3924-3940Subventions
Organisme : NCI NIH HHS
ID : R01 CA230913
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG048284
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA203702
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA215040
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA187417
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA211024
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
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