Autonomous action and cooperativity between the ONECUT2 transcription factor and its 3' untranslated region.
androgen metabolism
competitive endogenous RNA network
neuroendocrine prostate cancer
polycomb repressing complex
prostate cancer
Journal
Frontiers in cell and developmental biology
ISSN: 2296-634X
Titre abrégé: Front Cell Dev Biol
Pays: Switzerland
ID NLM: 101630250
Informations de publication
Date de publication:
2023
2023
Historique:
received:
15
04
2023
accepted:
16
05
2023
medline:
24
7
2023
pubmed:
24
7
2023
entrez:
24
7
2023
Statut:
epublish
Résumé
The transcription factor ONECUT2 (OC2) is a master transcriptional regulator operating in metastatic castration-resistant prostate cancer that suppresses androgen receptor activity and promotes neural differentiation and tumor cell survival. OC2 mRNA possesses an unusually long (14,575 nt), evolutionarily conserved 3' untranslated region (3' UTR) with many microRNA binding sites, including up to 26 miR-9 sites. This is notable because miR-9 targets many of the same genes regulated by the OC2 protein. Paradoxically, OC2 expression is high in tissues with high miR-9 expression. The length and complex secondary structure of OC2 mRNA suggests that it is a potent master competing endogenous RNA (ceRNA) capable of sequestering miRNAs. Here, we describe a novel role for OC2 3' UTR in lethal prostate cancer consistent with a function as a ceRNA. A plausible ceRNA network in OC2-driven tumors was constructed computationally and then confirmed in prostate cancer cell lines. Genes regulated by OC2 3' UTR exhibited high overlap (up to 45%) with genes driven by the overexpression of the OC2 protein in the absence of 3' UTR, indicating a cooperative functional relationship between the OC2 protein and its 3' UTR. These overlapping networks suggest an evolutionarily conserved mechanism to reinforce OC2 transcription by protection of OC2-regulated mRNAs from miRNA suppression. Both the protein and 3' UTR showed increased polycomb-repressive complex activity. The expression of OC2 3' UTR mRNA alone (without protein) dramatically increased the metastatic potential by
Identifiants
pubmed: 37484909
doi: 10.3389/fcell.2023.1206259
pii: 1206259
pmc: PMC10356556
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1206259Informations de copyright
Copyright © 2023 Steadman, You, Srinivas, Mouakkad, Yan, Kim, Venugopal, Tanaka and Freeman.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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