ZFTA–RELA ependymomas make itaconate to epigenetically drive fusion expression

ZFTA-RELA<sup>+</sup> ependymomas are malignant brain tumours defined by fusions formed between the putative chromatin remodeller ZFTA and the NF-κB mediator RELA<sup>1</sup>. Here we show that ZFTA-RELA<sup>+</sup> cells produce itaconate, a key macrophage-associated immunomodulatory metabolite<sup>2</sup>. Itaconate is generated by cis-aconitate decarboxylase 1 (ACOD1; also known as IRG1). However, the production of itaconate by tumour cells and its tumour-intrinsic role are not well established. ACOD1 is upregulated in a ZFTA-RELA-dependent manner. Functionally, itaconate enables a feed-forward system that is crucial for the maintenance of pathogenic ZFTA-RELA levels. Itaconate epigenetically activates ZFTA-RELA transcription by enriching for activating H3K4me3 via inhibition of the H3K4 demethylase KDM5. ZFTA-RELA<sup>+</sup> tumours enhance glutamine metabolism to supply carbons for itaconate synthesis. Antagonism of ACOD1 or glutamine metabolism reduces pathogenic ZFTA-RELA levels and is potently therapeutic in multiple in vivo models. Mechanistically, ZFTA-RELA epigenetically suppresses PTEN expression to upregulate PI3K-mTOR signalling, a known driver of glutaminolysis. Finally, suppression of ACOD1 or a combination of glutamine antagonism with PI3K-mTOR inhibition abrogates spinal metastasis. Our data demonstrate that ZFTA-RELA<sup>+</sup> ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA-RELA driver, which implicates itaconate as a candidate oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA<sup>+</sup> ependymomas. Our work has implications for future drug development to reduce pathogenic ZFTA-RELA expression for this brain tumour, and will advance our understanding of oncometabolites as a new class of therapeutic dependencies in cancers.

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Journal
Nature
Published
2026-02-04
DOI
https://doi.org/10.1038/s41586-025-10005-1
Citations
2
Primary Topic
Cancer, Hypoxia, and Metabolism
Type
article
Field-Weighted Citation Impact
49.63
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article

ZFTA–RELA ependymomas make itaconate to epigenetically drive fusion expression

Kulandaimanuvel Antony Michealraj, Matthew Pun, Simon Hoffman, Derek Dang et al.
2 citations
Nature
Cancer, Hypoxia, and Metabolism
49.63
article

ZFTA–RELA ependymomas make itaconate to epigenetically drive fusion expression

Kulandaimanuvel Antony Michealraj, Matthew Pun, Simon Hoffman, Derek Dang, Nicholas K. Foreman, Pooja Panwalkar, Yelena Wilson, Sanjana Eyunni, Robert Doherty, Mateus Mota, Deepak Nagrath, Jill Bayliss, Alexander R. Judkins, Sushanth Sunil, Thomas M. Vigil, Akash Deogharkar, Eleanor Young, Tatsuya Ozawa, Andrea M. Griesinger, Richard M. Mortensen, Stefan R. Sweha, Pranav Narayanan, Qiuyang Zhang, Joanna Lum, Olamide Animasahun, Siva Kumar Natarajan, Richard J. Gilbertson, Costas Andreas Lyssiotis, Debra Hawes, Fusheng Yang, Mehta Rs, Madison Clausen, Sameer Agnihotri, Sriram Venneti, Peter Sajjakulnukit, Arul M. Chinnaiyan, Erin Taya Hamanishi, Eric C. Holland, Carl Koschmann, Minal Nenwani, Andrea Franson, Abhijit Parolia, Michael Taylor, James Haggerty Skeans
article en
2 citations

Abstract

ZFTA-RELA<sup>+</sup> ependymomas are malignant brain tumours defined by fusions formed between the putative chromatin remodeller ZFTA and the NF-κB mediator RELA<sup>1</sup>. Here we show that ZFTA-RELA<sup>+</sup> cells produce itaconate, a key macrophage-associated immunomodulatory metabolite<sup>2</sup>. Itaconate is generated by cis-aconitate decarboxylase 1 (ACOD1; also known as IRG1). However, the production of itaconate by tumour cells and its tumour-intrinsic role are not well established. ACOD1 is upregulated in a ZFTA-RELA-dependent manner. Functionally, itaconate enables a feed-forward system that is crucial for the maintenance of pathogenic ZFTA-RELA levels. Itaconate epigenetically activates ZFTA-RELA transcription by enriching for activating H3K4me3 via inhibition of the H3K4 demethylase KDM5. ZFTA-RELA<sup>+</sup> tumours enhance glutamine metabolism to supply carbons for itaconate synthesis. Antagonism of ACOD1 or glutamine metabolism reduces pathogenic ZFTA-RELA levels and is potently therapeutic in multiple in vivo models. Mechanistically, ZFTA-RELA epigenetically suppresses PTEN expression to upregulate PI3K-mTOR signalling, a known driver of glutaminolysis. Finally, suppression of ACOD1 or a combination of glutamine antagonism with PI3K-mTOR inhibition abrogates spinal metastasis. Our data demonstrate that ZFTA-RELA<sup>+</sup> ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA-RELA driver, which implicates itaconate as a candidate oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA<sup>+</sup> ependymomas. Our work has implications for future drug development to reduce pathogenic ZFTA-RELA expression for this brain tumour, and will advance our understanding of oncometabolites as a new class of therapeutic dependencies in cancers.

Nature
University of Southern California (US), Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA), Children's Hospital of Philadelphia (US), Children's Hospital of Los Angeles (US), Howard Hughes Medical Institute (US), University of Pittsburgh (US), Baylor College of Medicine (US), University of Cambridge (GB), University of Michigan (US), Cancer Research UK (GB), Fred Hutch Cancer Center (US), Morgan Adams Foundation (US), Children's Hospital Colorado (US), Akron Children's Hospital (US), Michigan Medicine (US), Michigan Center for Translational Pathology (US), UPMC Hillman Cancer Center (US), Children's Hospital of Pittsburgh (US), BioSurfaces (United States) (US), Neurological Surgery (US), University of Colorado Anschutz Medical Campus (US), University of Colorado Denver (US)
Openalex Percentile: Top 0%
Cancer, Hypoxia, and Metabolism
49.63
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