Adenosylhomocysteinase drives epigenetic and metabolic reprogramming in ZFTA-RELA ependymoma
Year: 2026
Type: preprint
Abstract: Supratentorial ependymomas (ST-EPNs) are aggressive pediatric brain tumors predominantly driven by the recurrent ZFTA-RELA fusion, an oncogenic chromatin regulator that establishes an aberrant transcriptional program. Although metabolic pathways modulate epigenetic regulation by controlling the availability of metabolic cofactors, how ZFTA-RELA coordinates metabolic reprogramming with epigenetic regulation is not well understood. Here, we show that ZFTA-RELA-positive ependymomas exhibit enhanced methionine dependency, elevated adenosyl homocysteinase (AHCY) expression, and epigenetically control aspartate metabolism for tumor growth. Mechanistically, ZFTA-RELA upregulates AHCY, increasing cellular methylation potential which promotes H3K4me3-dependent expression of CAD, the first enzyme complex of de novo pyrimidine biosynthesis, while simultaneously enforcing H3K27me3 mediated repression of ASNS, which encodes asparagine synthetase. Through this coordinated epigenetic program, aspartate utilization is directed toward pyrimidine biosynthesis while endogenous asparagine production is limited. Restricting S-adenosylmethionine availability or genetically or pharmacologically inhibiting AHCY reverses these epigenetic states, leading to CAD downregulation, ASNS upregulation, impaired nucleotide synthesis, and suppression of tumor growth in vitro and in vivo. Similarly, EZH2 inhibition also restores ASNS expression and suppresses tumor proliferation. These findings suggest that ZFTA-RELA EPN maintain ASNS-low phenotype which conditionally make them dependent on extracellular asparagine. We further show that enhanced de novo pyrimidine synthesis not only supports nucleotide production but also provides UDP-sugars required for N-glycosylation and stabilization of the asparagine transporter SLC1A5, thereby promoting extracellular asparagine uptake and tumor proliferation. Collectively, our findings identify AHCY as a critical metabolic regulator of epigenetic and metabolic reprogramming that drives pyrimidine synthesis and establishes extracellular asparagine dependency, revealing actionable metabolic vulnerabilities in ZFTA-RELA-positive ST-EPNs. Key Findings: phenotype and dependence on extracellular asparagine Enhanced de novo pyrimidine biosynthesis fuels nucleotide synthesis and SLC1A5-dependent asparagine uptakeTargeting de novo pyrimidine biosynthesis and depleting extracellular asparagine reveal actionable vulnerabilities in ZFTA-RELA ST-EPN.
Authors: Navneesh Yadav, Olivia Pelcher, Raja G.R. Mooli, Robert B. Cameron, Alberto Delaidelli, Kannan B.N. Rao, Bhagyalakshmi Manikandan, Senna Visser, Antonio C.T. Cobos, Vishal Parmar, Yuvraj Kayola, Siva K. Natarajan, Yash Patel, Jiao Zhang, Hardik Shah, Subrahmanya D. Vallabhapurapu, Saifur R. Khan, Aaron Y. Mochizuki, Kalil G. Abdullah, Baoli Hu, Calixto-Hope G. Lucas, Philipp Sievers, Felix Sahm, Andrew M. Donson, Nicholas K. Foreman, Martine F. Roussel, Thomas M. Pearce, Peter Dirks, Kristian W. Pajtler, Stephen C. Mack, Jeremy Rich, Richard J. Gilbertson, Eric C. Holland, Sadeesh K. Ramakrishnan, Taylor J. Abel, Srinivas Ramachandran, Sameer Agnihotri, Bokai Zhu, Sriram Venneti, Brandon Faubert, Michael D. Taylor, Esther Hulleman, Ian F. Pollack, Timothy Phoenix, Kulandaimanuvel Antony Michealraj
Institutions: University of Pittsburgh, Children's Hospital of Pittsburgh, University of Chicago, Brigham and Women's Hospital, Harvard University, Princess Máxima Center, University of Michigan, Michigan Medicine, Baylor College of Medicine, Texas Children's Hospital, University of Chicago Medicine Comprehensive Cancer Center, UPMC Health System, University of Pittsburgh Medical Center, University of Cincinnati, Northwell Health, Johns Hopkins University, Johns Hopkins Medicine, German Cancer Research Center, University Hospital Heidelberg, Morgan Adams Foundation, University of Colorado Anschutz, St. Jude Children's Research Hospital, University of Toronto, Deutsches Konsortium für Translationale Krebsforschung, University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, University of Cambridge, Cancer Research UK, Fred Hutch Cancer Center, Dan L Duncan Comprehensive Cancer Center, UPMC Hillman Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7220862678