CDK5RAP3 is a co-factor for the oncogenic transcription factor STAT3.
Biomarkers
Breast Neoplasms
/ genetics
Carcinogenesis
Cell Cycle Proteins
/ metabolism
Cell Line, Tumor
Cytokines
/ metabolism
Female
Gene Expression Regulation
Genes, Reporter
Humans
Promoter Regions, Genetic
Protein Binding
Protein Transport
RNA Interference
STAT3 Transcription Factor
/ metabolism
Tumor Suppressor Proteins
/ metabolism
Tyrosine
/ metabolism
Journal
Neoplasia (New York, N.Y.)
ISSN: 1476-5586
Titre abrégé: Neoplasia
Pays: United States
ID NLM: 100886622
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
02
05
2019
revised:
13
10
2019
accepted:
14
10
2019
pubmed:
26
11
2019
medline:
20
11
2020
entrez:
26
11
2019
Statut:
ppublish
Résumé
The transcription factor STAT3 regulates genes governing critical cellular processes such as proliferation, survival, and self-renewal. While STAT3 transcriptional function is activated rapidly and transiently in response to physiologic signals, through a variety of mechanisms it can become constitutively activated in the pathogenesis of cancer. This leads to chronic expression of genes that underlie malignant cellular behavior. However, STAT3 is known to interact with other proteins, which may modulate its function. Understanding these interactions can provide insights into novel aspects of STAT3 function and may also suggest strategies to therapeutically target the large number of cancers driven by constitutively activated STAT3. To identify critical modulators of STAT3 transcriptional function, we performed an RNA-interference based screen in a cell-based system that allows quantitative measurement of STAT3 activity. From this approach, we identified CDK5 kinase regulatory-subunit associated protein 3 (CDK5RAP3) as an enhancer of STAT3-dependent gene expression. We found that STAT3 transcriptional function is modulated by CDK5RAP3 in cancer cells, and silencing CDK5RAP3 reduces STAT3-mediated tumorigenic phenotypes including clonogenesis and migration. Mechanistically, CDK5RAP3 binds to STAT3-regulated genomic loci, in a STAT3-dependent manner. In primary human breast cancers, the expression of CDK5RAP3 expression was associated with STAT3 gene expression signatures as well as the expression of individual STAT3 target genes. These findings reveal a novel aspect of STAT3 transcriptional function and potentially provide both a biomarker of enhanced STAT3-dependent gene expression as well as a unique mechanism to therapeutically target STAT3.
Identifiants
pubmed: 31765941
pii: S1476-5586(19)30209-X
doi: 10.1016/j.neo.2019.10.002
pmc: PMC6881650
pii:
doi:
Substances chimiques
Biomarkers
0
CDK5RAP3 protein, human
0
Cell Cycle Proteins
0
Cytokines
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Tumor Suppressor Proteins
0
Tyrosine
42HK56048U
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
47-59Subventions
Organisme : NCI NIH HHS
ID : R01 CA160979
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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