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Cited by 19Cytokine Signaling Pathways and InteractionsProtein Tyrosine PhosphatasesTGF-β signaling in diseases

Necdin, a negative growth regulator, is a novel STAT3 target gene down-regulated in human cancer

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Haviland, Rachel, Eschrich, Steven, Bloom, Gregory, Ma, Yihong, Minton, Susan, Jove, Richard, Cress, W. Douglas·2011·PLoS ONE
DOI 10.1371/journal.pone.0024923PMC PMC3203112
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Abstract

Cytokine and growth factor signaling pathways involving STAT3 are frequently constitutively activated in many human primary tumors, and are known for the transcriptional role they play in controlling cell growth and cell cycle progression. However, the extent of STAT3's reach on transcriptional control of the genome as a whole remains an important question. We predicted that this persistent STAT3 signaling affects a wide variety of cellular functions, many of which still remain to be characterized. We took a broad approach to identify novel STAT3 regulated genes by examining changes in the genome-wide gene expression profile by microarray, using cells expressing constitutively-activated STAT3. Using computational analysis, we were able to define the gene expression profiles of cells containing activated STAT3 and identify candidate target genes with a wide range of biological functions. Among these genes we identified Necdin, a negative growth regulator, as a novel STAT3 target gene, whose expression is down-regulated at the mRNA and protein levels when STAT3 is constitutively active. This repression is STAT3 dependent, since inhibition of STAT3 using siRNA restores Necdin expression. A STAT3 DNA-binding site was identified in the Necdin promoter and both EMSA and chromatin immunoprecipitation confirm binding of STAT3 to this region. Necdin expression has previously been shown to be down-regulated in a melanoma and a drug-resistant ovarian cancer cell line. Further analysis of Necdin expression demonstrated repression in a STAT3-dependent manner in human melanoma, prostate and breast cancer cell lines. These results suggest that STAT3 coordinates expression of genes involved in multiple metabolic and biosynthetic pathways, integrating signals that lead to global transcriptional changes and oncogenesis. STAT3 may exert its oncogenic effect by up-regulating transcription of genes involved in promoting growth and proliferation, but also by down-regulating expression of negative regulators of the same cellular processes, such as Necdin.

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Authors
Haviland, R., Eschrich, S., Bloom, G., Ma, Y., Minton, S., Jove, R., & Cress, W. D.
Affiliations
  • Moffitt Cancer Center (US)
  • City Of Hope National Medical Center (US)
Corresponding author
  • Jove, Richard
  • Cress, W. Douglas
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-10-27
Volume
6
Issue
10
Pages
e24923
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0024923
PMC
PMC3203112
OpenAlex
W1993094865
Cited by
19
References
3
Citations by year
2025: 1 · 2022: 1 · 2021: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 4 · 2014: 5 · 2013: 1 · 2012: 3
FWCI
1.42
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Moffitt Cancer Center
  • National Cancer Institute (CA115674, R01CA115674, P30CA076292)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
NDN, STAT3, STAT3 target genes, transcriptional repression, melanoma, ovarian cancer, prostate cancer, breast cancer, carcinogenesis, gene expression profiling, promoter binding, siRNA knockdown
MeSH terms
Binding Sites, Humans, Neoplasms, Nerve Tissue Proteins, Nuclear Proteins, Promoter Regions, Genetic, Transcription, Genetic, Down-Regulation, Genome, Human, Gene Expression Regulation, Neoplastic, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, STAT3 Transcription Factor

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