{
  "abstract": "SETD2 is a critical tumor suppressor in lung cancer that catalyzes histone H3 lysine 36 (H3K36) trimethylation. Oncogenic histone H3 alleles, including H3K36M, causally drive cancer formation by dominantly inhibiting SETD2 and other H3K36 methyltransferases. Here we show that expression of the H3K36M oncogene paradoxically suppresses tumor growth in KRAS-driven lung cancer by promoting transcription of repetitive elements and accumulation of cytoplasmic dsRNA, activating antiviral-like immune clearance. Unexpectedly, all attendant effects of H3K36M expression require SETD2 activity despite widespread loss of H3K36 trimethylation. Reducing H3K36 dimethylation through genetic or pharmacologic attenuation of NSD2 phenocopies H3K36M expression, revealing NSD2 as the relevant target through which H3K36M triggers immune activation. Mechanistically, H3K36M expression or NSD2 attenuation reveals a SETD2-dependent mechanism that limits EZH2-mediated repression of repetitive elements, enabling dsRNA accumulation and immune activation. These findings establish opposing roles for NSD2- and SETD2-dependent H3K36 methylation in lung tumor immunity and reveal an NSD2-SETD2-EZH2 axis that can be targeted to modulate viral mimicry and immune surveillance in cancer.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.",
    "Cell and Molecular Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.",
    "Department of Bioengineering, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.",
    "Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.",
    "Bioengineering Graduate Group, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.",
    "Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA.",
    "Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.",
    "Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. dfeldser@upenn.edu.",
    "Cell and Molecular Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. dfeldser@upenn.edu.",
    "Bioengineering Graduate Group, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA. dfeldser@upenn.edu.",
    "Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA. dfeldser@upenn.edu."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Amy C Gladstein",
      "orcid": "0000-0002-3318-6695"
    },
    {
      "affs": [
        0
      ],
      "name": "Akino Mercy Charles Solomon"
    },
    {
      "affs": [
        1,
        2,
        3
      ],
      "name": "Carson D Poltorack"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Sharan Venkatesh"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Keren M Adler"
    },
    {
      "affs": [
        0
      ],
      "name": "Maggie R Robertson"
    },
    {
      "affs": [
        5
      ],
      "name": "Stephanie Stransky",
      "orcid": "0000-0003-0844-2754"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Valerie M Irizarry-Negron",
      "orcid": "0000-0002-8542-726X"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Dain A Ruiz",
      "orcid": "0000-0001-6080-8288"
    },
    {
      "affs": [
        0
      ],
      "name": "Dingwen Tao"
    },
    {
      "affs": [
        0
      ],
      "name": "Nelson F Freeburg"
    },
    {
      "affs": [
        5
      ],
      "name": "Simone Sidoli",
      "orcid": "0000-0001-9073-6641"
    },
    {
      "affs": [
        0,
        1,
        4,
        6
      ],
      "name": "Irfan A Asangani",
      "orcid": "0000-0001-5381-1702"
    },
    {
      "affs": [
        1,
        2,
        3
      ],
      "name": "Sydney M Shaffer",
      "orcid": "0000-0003-3539-9886"
    },
    {
      "affs": [
        7,
        8,
        9,
        10
      ],
      "name": "David M Feldser",
      "orcid": "0000-0001-5975-864X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cg11nfpybsc2k.bib",
  "cited_by": 0,
  "doi": "10.1038/s41467-026-76657-3",
  "fulltext_url": "https://europepmc.org/articles/PMC13669384",
  "id": "cg11nfpybsc2k",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://europepmc.org/article/MED/42875424",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Genomics and Chromatin Dynamics"
    ]
  ],
  "openalex": "W7212495282",
  "pdf_url": "https://europepmc.org/articles/PMC13669384?pdf=render",
  "pmcid": "PMC13669384",
  "pmid": "42875424",
  "published": "2026-09-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/cg11nfpybsc2k.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:18Z",
      "native_id": "MED:42875424",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42875424"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Genomics and Chromatin Dynamics",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Antagonistic roles of histone H3 lysine methyltransferases dictate tumor immune surveillance.",
  "title_text": "Antagonistic roles of histone H3 lysine methyltransferases dictate tumor immune surveillance.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:18Z",
  "url": "https://research.draconitic.com/paper/cg11nfpybsc2k",
  "venue": "Nature communications",
  "versions": []
}