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Cited by 380Cytokine Signaling Pathways and InteractionsEpigenetics and DNA MethylationMechanisms of cancer metastasis

SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer

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He, Biao, You, Liang, Uematsu, Kazutsugu, Zang, Keling, Xu, Zhidong, Lee, Amie Y., Costello, Joseph F., McCormick, Frank +1 more·2003·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2232790100PMC PMC283558
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Abstract

Lung cancer is the leading cause of cancer death in the world, but the molecular mechanisms for its development have not been well characterized. The suppressors of cytokine signaling (SOCS) are inhibitors of cytokine signaling that function via the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Eight SOCS proteins with similar structures have been identified so far. SOCS family members, however, have distinct mechanisms of inhibition of JAK/STAT signaling. Abnormalities of the JAK/STAT pathway are associated with cancer. Inhibition of signaling results in growth suppression in various cell types. Recently, the involvement of SOCS-1 in carcinogenesis has been reported. Here, we report identification of frequent hypermethylation in CpG islands of the functional SOCS-3 promoter that correlates with its transcription silencing in cell lines (lung cancer, breast cancer, and mesothelioma) and primary lung cancer tissue samples. Restoration of SOCS-3 in lung cancer cells where SOCS-3 was methylation-silenced resulted in the down-regulation of active STAT3, induction of apoptosis, and growth suppression. Our results suggest that methylation silencing of SOCS-3 is one of the important mechanisms of constitutive activation of the JAK/STAT pathway in cancer pathogenesis. The data also suggest that SOCS-3 therapy may be useful in the treatment of cancer.

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  • Activation of STAT3 in human cancers can result from genomic or epigenomic inactivation of proteins that normally downregulate STAT3 activity.

    “Conversely, activation of STAT3 in human cancers can result from genomic or epigenomic inactivation of proteins that normally downregulate STAT3 activity.”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [61]

    The Abstract and Discussion report that promoter hypermethylation silences SOCS-3, a negative regulator of JAK/STAT signaling, and that restoring SOCS-3 reduces active STAT3 in lung cancer cells. This supports epigenetic inactivation as a possible route to STAT3 activation, but the supplied passages do not establish genomic inactivation as another route. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Hypermethylation of the SOCS3 promoter and reduced SOCS3 expression is associated with proliferative diseases.

    “Additionally, hypermethylation of the SOCS3 promoter and reduced SOCS3 expression is associated with proliferative diseases [39, 40].”

    From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [39]

  • In lung cancer, SOCS3 is frequently downregulated by promoter hypermethylation, and restoration of SOCS3 expression leads to downregulation of active STAT3, induction of apoptosis, and suppression of cell growth.

    “In lung cancer, for example, SOCS3 is frequently downregulated by promoter hypermethylation, and restoration of SOCS3 expression in cells where it was previously silenced leads to downregulation of active STAT3, induction of apoptosis, and suppression of cell growth.61”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [61]

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Cited by

Sorted by citations

Authors
He, B., You, L., Uematsu, K., Zang, K., Xu, Z., Lee, A. Y., Costello, J. F., McCormick, F., & Jablons, D. M.
Affiliations
University of California, San Francisco (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2003-11-14
Volume
100
Issue
24
Pages
14133-14138
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2232790100
PMC
PMC283558
OpenAlex
W1981745443
Cited by
380
References
1
Citations by year
2026: 6 · 2025: 3 · 2024: 4 · 2023: 14 · 2022: 5 · 2021: 15 · 2020: 13 · 2019: 14 · 2018: 8 · 2017: 16 · 2016: 26 · 2015: 20 · 2014: 18 · 2013: 18 · 2012: 24
FWCI
7.03
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords
SOCS3, suppressor of cytokine signaling, DNA hypermethylation, promoter methylation, CpG islands, transcriptional silencing, lung cancer, JAK/STAT signaling, STAT3 activation, apoptosis, cell growth inhibition, mesothelioma, breast cancer, cancer therapy
MeSH terms
Suppressor of Cytokine Signaling 3 Protein, Base Sequence, Carcinoma, Non-Small-Cell Lung, Cell Division, DNA-Binding Proteins, DNA, Neoplasm, Humans, Lung Neoplasms, Promoter Regions, Genetic, Proteins, Repressor Proteins, Transcription Factors, Signal Transduction, Trans-Activators, Apoptosis, DNA Methylation, Gene Silencing, Cell Line, Tumor, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins

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