article Open Access (gold) EN 2026-02-21

Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity

Richa Singh, Varadha Balaji Venkadakrishnan, Eddie L. Imada, Yasutaka Yamada, Nicholas J. Brady, Kate Dunmore, Richard Garner, Matthew A. Booker, Brian Hanratty, Michael C. Haffner, Michael Tolstorukov, Luigi Marchionni, Brian D. Robinson, David S. Rickman, Himisha Beltran

Nature Communications, Vol. 17, Issue 1 (2026)

Cornell University, Weill Cornell Medicine, Broad Institute, Harvard University, Dana-Farber Cancer Institute, Fred Hutch Cancer Center, University of Washington

DOI: 10.1038/s41467-026-69308-0 PMID: 41720768

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Abstract

Prostate cancer lineage plasticity is associated with changes in DNA methylation and enhancer of zeste homolog 2 (EZH2) activity. How these epigenetic programs functionally interact to modulate transcriptional reprogramming in neuroendocrine prostate cancer (NEPC) is not well understood. In this study, we demonstrate that hypomethylated regions of DNA preferentially accumulate the repressive mark, H3K27me3. We established an NEPC mouse model with deletion of Ezh2 in the background of Pten and Rb1 loss plus human MYCN overexpression. Deletion or pharmacological inhibition of EZH2 in NEPC murine or patient-derived models leads to a genome-wide rewiring of DNA methylation, characterized by hypomethylation and upregulation of neuroendocrine-lineage genes along with hypermethylation and repression of polycomb repressive complex 2 (PRC2) targets. On the other hand, deletion of DNA methyltransferase 1 (DNMT1) results in significant changes in H3K27me3 distribution, particularly affecting bivalent promoters bearing both H3K27me3 and active H3K4me3 marks. In NEPC models, neuroendocrine-lineage genes are repressed upon DNMT1 deletion associated with increased H3K27me3. Conversely, in prostate adenocarcinoma models, DNMT1 deletion leads to de-repression of neuroendocrine lineage genes with a loss of H3K27me3 marks. Our findings reveal a functional interplay between two repressive epigenetic machineries that mediates lineage plasticity in prostate cancer.

Topics

Prostate Cancer Treatment and Research 0.72 Epigenetics and DNA Methylation 0.20 Prostate Cancer Diagnosis and Treatment 0.04

Field: Medicine · Subfield: Pulmonary and Respiratory Medicine

Keywords

H3K4me3,DNA methylation,EZH2,Epigenetics,PRC2,Reprogramming,Histone,Histone methyltransferase,DNMT1,DNA methyltransferase

MeSH Terms

Enhancer of Zeste Homolog 2 ProteinEnhancer of Zeste Homolog 2 ProteinEnhancer of Zeste Homolog 2 ProteinEnhancer of Zeste Homolog 2 ProteinEnhancer of Zeste Homolog 2 ProteinEnhancer of Zeste Homolog 2 ProteinEnhancer of Zeste Homolog 2 ProteinEnhancer of Zeste Homolog 2 Protein

UN Sustainable Development Goals

Good health and well-being (0.61)

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Citations by Year

2026
5

APA

Richa Singh, Varadha Balaji Venkadakrishnan, Eddie L. Imada, Yasutaka Yamada, Nicholas J. Brady, Kate Dunmore, Richard Garner, Matthew A. Booker, Brian Hanratty, Michael C. Haffner, Michael Tolstorukov, Luigi Marchionni, Brian D. Robinson, David S. Rickman, Himisha Beltran (2026). Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity. Nature Communications, 17(1). https://doi.org/10.1038/s41467-026-69308-0

MLA

Richa Singh, et al. "Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity." Nature Communications, vol. 17, no. 1, 2026. https://doi.org/10.1038/s41467-026-69308-0

Chicago

Richa Singh, Varadha Balaji Venkadakrishnan, Eddie L. Imada, Yasutaka Yamada, Nicholas J. Brady, Kate Dunmore, Richard Garner, Matthew A. Booker, Brian Hanratty, Michael C. Haffner, Michael Tolstorukov, Luigi Marchionni, Brian D. Robinson, David S. Rickman, Himisha Beltran. "Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity." Nature Communications 17, no. 1 (2026). https://doi.org/10.1038/s41467-026-69308-0

BibTeX

@article{singh2026,
  title = { Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity },
  author = { Richa Singh and Varadha Balaji Venkadakrishnan and Eddie L. Imada and Yasutaka Yamada and Nicholas J. Brady and Kate Dunmore and Richard Garner and Matthew A. Booker and Brian Hanratty and Michael C. Haffner and Michael Tolstorukov and Luigi Marchionni and Brian D. Robinson and David S. Rickman and Himisha Beltran },
  journal = { Nature Communications },
  year = { 2026 },
  volume = { 17 },
  number = { 1 },
  doi = { 10.1038/s41467-026-69308-0 }
}

RIS

TY  - JOUR
TI  - Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity
AU  - Richa Singh
AU  - Varadha Balaji Venkadakrishnan
AU  - Eddie L. Imada
AU  - Yasutaka Yamada
AU  - Nicholas J. Brady
AU  - Kate Dunmore
AU  - Richard Garner
AU  - Matthew A. Booker
AU  - Brian Hanratty
AU  - Michael C. Haffner
AU  - Michael Tolstorukov
AU  - Luigi Marchionni
AU  - Brian D. Robinson
AU  - David S. Rickman
AU  - Himisha Beltran
JO  - Nature Communications
PY  - 2026
VL  - 17
IS  - 1
DO  - 10.1038/s41467-026-69308-0
ER  -

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