Antagonistic roles of histone H3 lysine methyltransferases dictate tumor immune surveillance.
11 affiliations
- 1Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- 2Cell and Molecular Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- 3Department of Bioengineering, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- 4Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- 5Bioengineering Graduate Group, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.
- 6Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA.
- 7Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.
- 8Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
- 9Cell and Molecular Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
- 10Bioengineering Graduate Group, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
- 11Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
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.
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BibTeX
@article{gladstein2026antagonistic,
title = {{Antagonistic roles of histone H3 lysine methyltransferases dictate tumor immune surveillance.}},
author = {Amy C Gladstein and Akino Mercy Charles Solomon and Carson D Poltorack and Sharan Venkatesh and Keren M Adler and Maggie R Robertson and Stephanie Stransky and Valerie M Irizarry-Negron and Dain A Ruiz and Dingwen Tao and Nelson F Freeburg and Simone Sidoli and Irfan A Asangani and Sydney M Shaffer and David M Feldser},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-76657-3},
url = {https://europepmc.org/article/MED/42875424},
note = {CC BY},
}
RIS
TY - JOUR
TI - Antagonistic roles of histone H3 lysine methyltransferases dictate tumor immune surveillance.
AU - Amy C Gladstein
AU - Akino Mercy Charles Solomon
AU - Carson D Poltorack
AU - Sharan Venkatesh
AU - Keren M Adler
AU - Maggie R Robertson
AU - Stephanie Stransky
AU - Valerie M Irizarry-Negron
AU - Dain A Ruiz
AU - Dingwen Tao
AU - Nelson F Freeburg
AU - Simone Sidoli
AU - Irfan A Asangani
AU - Sydney M Shaffer
AU - David M Feldser
PY - 2026
DA - 2026/09/14
JO - Nature communications
DO - 10.1038/s41467-026-76657-3
UR - https://europepmc.org/article/MED/42875424
AB - 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.
SN - 2041-1723
ER -