The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer.
Androgen Antagonists
/ therapeutic use
Animals
Benzamides
/ pharmacology
Biomarkers, Tumor
/ metabolism
Carcinoma, Neuroendocrine
/ diagnosis
Cell Line, Tumor
Cell Lineage
/ genetics
Cell Nucleus
/ metabolism
Cell Plasticity
/ genetics
Cell Proliferation
/ genetics
Cohort Studies
DNA Methylation
/ genetics
Disease Models, Animal
Drug Resistance, Neoplasm
/ genetics
Epigenesis, Genetic
/ drug effects
Gene Expression Regulation, Neoplastic
Genome, Human
Histones
/ metabolism
Humans
Male
Neoplasm Grading
Neoplasm Invasiveness
Neoplastic Stem Cells
/ metabolism
Nitriles
/ pharmacology
Organoids
/ metabolism
Phenylthiohydantoin
/ pharmacology
Phylogeny
Polycomb Repressive Complex 2
/ metabolism
Promoter Regions, Genetic
/ genetics
Prostatic Neoplasms
/ diagnosis
Protein Isoforms
/ genetics
RNA, Long Noncoding
/ genetics
Receptors, Androgen
/ metabolism
SOXB1 Transcription Factors
/ metabolism
Transcription, Genetic
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
21 12 2021
21 12 2021
Historique:
received:
05
11
2019
accepted:
22
10
2021
entrez:
22
12
2021
pubmed:
23
12
2021
medline:
12
1
2022
Statut:
epublish
Résumé
Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between the long noncoding RNA (lncRNA) H19 and NEPC, with the longest isoform highly expressed in NEPC. H19 regulates PCa lineage plasticity by driving a bidirectional cell identity of NE phenotype (H19 overexpression) or luminal phenotype (H19 knockdown). It contributes to treatment resistance, with the knockdown of H19 re-sensitizing PCa to ADT. It is also essential for the proliferation and invasion of NEPC. H19 levels are negatively regulated by androgen signaling via androgen receptor (AR). When androgen is absent SOX2 levels increase, driving H19 transcription and facilitating transdifferentiation. H19 facilitates the PRC2 complex in regulating methylation changes at H3K27me3/H3K4me3 histone sites of AR-driven and NEPC-related genes. Additionally, this lncRNA induces alterations in genome-wide DNA methylation on CpG sites, further regulating genes associated with the NEPC phenotype. Our clinical data identify H19 as a candidate diagnostic marker and predictive marker of NEPC with elevated H19 levels associated with an increased probability of biochemical recurrence and metastatic disease in patients receiving ADT. Here we report H19 as an early upstream regulator of cell fate, plasticity, and treatment resistance in NEPC that can reverse/transform cells to a treatable form of PCa once therapeutically deactivated.
Identifiants
pubmed: 34934057
doi: 10.1038/s41467-021-26901-9
pii: 10.1038/s41467-021-26901-9
pmc: PMC8692330
doi:
Substances chimiques
AR protein, human
0
Androgen Antagonists
0
Benzamides
0
Biomarkers, Tumor
0
H19 long non-coding RNA
0
Histones
0
Nitriles
0
Protein Isoforms
0
RNA, Long Noncoding
0
Receptors, Androgen
0
SOXB1 Transcription Factors
0
Phenylthiohydantoin
2010-15-3
enzalutamide
93T0T9GKNU
Polycomb Repressive Complex 2
EC 2.1.1.43
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
7349Subventions
Organisme : NCI NIH HHS
ID : R01 CA173200
Pays : United States
Organisme : CIHR
ID : PJT-175238
Pays : Canada
Organisme : NCI NIH HHS
ID : R37 CA241486
Pays : United States
Organisme : CIHR
ID : PJT-153073
Pays : Canada
Organisme : NCI NIH HHS
ID : P30 CA023074
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA211024
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA232105
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021. The Author(s).
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