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Cited by 340Cytokine Signaling Pathways and InteractionsGenomics and Chromatin DynamicsEpigenetics and DNA Methylation

Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes

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Yang, Jinbo, Huang, Jing, Dasgupta, Maupali, Sears, Nathan, Miyagi, Masaru, Wang, Benlian, Chance, Mark R., Chen, Xing +8 more·2010·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1016147107PMC PMC3003019
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Abstract

Following its tyrosine phosphorylation, STAT3 is methylated on K140 by the histone methyl transferase SET9 and demethylated by LSD1 when it is bound to a subset of the promoters that it activates. Methylation of K140 is a negative regulatory event, because its blockade greatly increases the steady-state amount of activated STAT3 and the expression of many (i.e., SOCS3 ) but not all (i.e., CD14 ) STAT3 target genes. Biological relevance is shown by the observation that overexpression of SOCS3 when K140 cannot be methylated blocks the ability of cells to activate STAT3 in response to IL-6. K140 methylation does not occur with mutants of STAT3 that do not enter nuclei or bind to DNA. Following treatment with IL-6, events at the SOCS3 promoter occur in an ordered sequence, as shown by chromatin immunoprecipitations. Y705-phosphoryl-STAT3 binds first and S727 is then phosphorylated, followed by the coincident binding of SET9 and dimethylation of K140, and lastly by the binding of LSD1. We conclude that the lysine methylation of promoter-bound STAT3 leads to biologically important down-regulation of the dependent responses and that SET9, which is known to help provide an activating methylation mark to H3K4, is recruited to the newly activated SOCS3 promoter by STAT3.

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  • pS727 in the nucleus is required for recruitment of histone lysine methyltransferase SET9, which dimethylates STAT3 at Lys140, leading to pY705 inhibition.

    “Mechanistically, pS727 in the nucleus is required for the recruitment of histone lysine methyltransferase SET9, which dimethylates STAT3 at Lys140, leading to pY705 inhibition (Yang et al., 2010).”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Yang et al., 2010

    The Results show that nuclear, DNA-bound STAT3 requires S727 phosphorylation for K140 dimethylation, and that SET9 is required for that modification. They also report greater and more sustained Y705 phosphorylation when K140 cannot be methylated. But the Discussion presents recruitment of SET9 by phosphorylated S727 only as a possibility, and the Results say the mechanistic link between K140 methylation and Y705 phosphorylation is unclear. (LLM, conf=0.90)

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Sorted by citations

Authors
Yang, J., Huang, J., Dasgupta, M., Sears, N., Miyagi, M., Wang, B., Chance, M. R., Chen, X., Du, Y., Wang, Y., An, L., Wang, Q., Lu, T., Zhang, X., Wang, Z., & Stark, G. R.
Affiliations
  • Cleveland Clinic (US)
  • National Institutes of Health (US)
  • Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
  • Case Western Reserve University (US)
  • Center for Proteomics and Bioinformatics and
  • Lanzhou University (CN)
  • Case Comprehensive Cancer Center (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2010-11-23
Volume
107
Issue
50
Pages
21499-21504
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1016147107
PMC
PMC3003019
OpenAlex
W2014596538
Cited by
340
References
1
Citations by year
2026: 16 · 2025: 20 · 2024: 16 · 2023: 14 · 2022: 25 · 2021: 25 · 2020: 27 · 2019: 24 · 2018: 27 · 2017: 21 · 2016: 23 · 2015: 28 · 2014: 23 · 2013: 24 · 2012: 18
FWCI
8.23
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)
  • Lanzhou University Institutional Repository (submittedVersion, cc-by-nc)
Funders
  • Program for New Century Excellent Talents in University
  • National Cancer Institute (P01-CA 62220, R01CA127590, P01CA062220)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
STAT3, lysine methylation, LSD1, histone demethylation, SOCS3, IL-6 signaling, tyrosine phosphorylation, transcriptional regulation, chromatin recruitment, negative transcriptional regulation
MeSH terms
Suppressor of Cytokine Signaling 3 Protein, Cell Line, Histones, Humans, Lysine, Methylation, Promoter Regions, Genetic, Histone-Lysine N-Methyltransferase, Interleukin-6, Active Transport, Cell Nucleus, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Histone Demethylases

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