2. Academic Validation
  3. NAT10-dependent N4-acetylcytidine reprograms R-loops and promotes cancer stem cell growth

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

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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