CBX7 binds the E-box to inhibit TWIST-1 function and inhibit tumorigenicity and metastatic potential.
Carcinogenesis
/ genetics
Cell Line, Tumor
Epithelial-Mesenchymal Transition
Female
Gene Expression Regulation, Neoplastic
Humans
Neoplasm Metastasis
Neoplasm Proteins
/ genetics
Nuclear Proteins
/ biosynthesis
Ovarian Neoplasms
/ genetics
Polycomb Repressive Complex 1
/ genetics
Response Elements
Transcription, Genetic
Twist-Related Protein 1
/ biosynthesis
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
10
07
2019
accepted:
11
03
2020
revised:
05
03
2020
pubmed:
25
3
2020
medline:
25
11
2020
entrez:
25
3
2020
Statut:
ppublish
Résumé
Deaths from ovarian cancer usually occur when patients succumb to overwhelmingly numerous and widespread micrometastasis. Whereas epithelial-mesenchymal transition is required for epithelial ovarian cancer cells to acquire metastatic potential, the cellular phenotype at secondary sites and the mechanisms required for the establishment of metastatic tumors are not fully determined. Using in vitro and in vivo models we show that secondary epithelial ovarian cancer cells (sEOC) do not fully reacquire the molecular signature of the primary epithelial ovarian cancer cells from which they are derived. Despite displaying an epithelial morphology, sEOC maintains a high expression of the mesenchymal effector, TWIST-1. TWIST-1 is however transcriptionally nonfunctional in these cells as it is precluded from binding its E-box by the PcG protein, CBX7. Deletion of CBX7 in sEOC was sufficient to reactivate TWIST-1-induced transcription, prompt mesenchymal transformation, and enhanced tumorigenicity in vivo. This regulation allows secondary tumors to achieve an epithelial morphology while conferring the advantage of prompt reversal to a mesenchymal phenotype upon perturbation of CBX7. We also describe a subclassification of ovarian tumors based on CBX7 and TWIST-1 expression, which predicts clinical outcomes and patient prognosis.
Identifiants
pubmed: 32205869
doi: 10.1038/s41388-020-1269-5
pii: 10.1038/s41388-020-1269-5
pmc: PMC8343988
mid: NIHMS1575440
doi:
Substances chimiques
CBX7 protein, human
0
Neoplasm Proteins
0
Nuclear Proteins
0
TWIST1 protein, human
0
Twist-Related Protein 1
0
Polycomb Repressive Complex 1
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3965-3979Subventions
Organisme : NCI NIH HHS
ID : R01 CA199004
Pays : United States
Organisme : NIA NIH HHS
ID : T35 AG049685
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
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