NAT10-dependent N4-acetylcytidine reprograms R-loops and promotes cancer stem cell growth

  • Cell Rep. 2026 Jun 23;45(6):117408. doi: 10.1016/j.celrep.2026.117408.
Xujia Wu  1 ,  Donghai Wang  2 ,  Suchet Taori  3 ,  Weichi Wu  2 ,  Deobrat Dixit  4 ,  Deguan Lv  3 ,  Steven J Mullett  5 ,  Stacy L Gelhaus  5 ,  Fanen Yuan  3 ,  Po Zhang  3 ,  Tengfei Huang  2 ,  Huairui Yuan  3 ,  Qiulian Wu  2 ,  Jeremy N Rich  6
Affiliations
  • 1. Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 2. Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
  • 3. Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • 4. Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
  • 5. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA.
  • 6. Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA. Electronic address: [email protected].
PMID: 42228575 DOI: 10.1016/j.celrep.2026.117408
Abstract

R-loop remodeling dynamically regulates chromatin states and gene expression; however, its exploitation by Cancer to sustain self-renewal and malignancy remains poorly understood. Here, we find that glioblastoma (GBM) stem cells (GSCs) display highly active R-loops compared to differentiated progeny and neural stem cells. Genome-wide mapping reveals cell-specific enrichment and spatial accumulation of R-loops at promoter-proximal regions in GSCs, correlating with active transcription and open chromatin. We identify N-acetyltransferase 10 (NAT10) as a high-affinity R-loop-binding protein in GSCs, where it is overexpressed downstream of OLIG1. NAT10 catalyzes widespread N4-acetylcytidine (ac4C) deposition on the RNA strand of R-loops, stabilizing promoter-associated R-loops and facilitating open chromatin to sustain self-renewal through core stemness regulators, including EGR1. NAT10 knockdown suppresses GSC proliferation and maintenance in vitro and attenuates tumor growth in vivo. Pharmacological inhibition of NAT10/ac4C-modified R-loops using remodelin phenocopies NAT10 genetic targeting, demonstrating therapeutic promise for targeting Cancer.

Keywords
CP: cancer; CP: neuroscience; EGR1; NAT10; R-loop remodelin; ac(4)C; cancer stem cell; epitranscriptomics; glioblastoma; glioblastoma stem cell.
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