2. Academic Validation
  3. NAT10 promotes cancer metastasis by modulating p300/CBP activity through chromatin-associated tRNA

NAT10 promotes cancer metastasis by modulating p300/CBP activity through chromatin-associated tRNA

  • Mol Cell. 2025 Dec 18;85(24):4526-4544.e18. doi: 10.1016/j.molcel.2025.11.010.
Ruhul Amin 1,  Ngoc-Han Ha 2,  Tinghu Qiu 2,  Ronald Holewinski 3,  Khiem C Lam 4,  Amélie Daugherty-Lopès 4,  Huaitian Liu 5,  Andy D Tran 6,  Maxwell P Lee 7,  Thorkell Andresson 3,  Romina S Goldszmid 4,  Kent W Hunter 8
Affiliations

Affiliations

  • 1 Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: [email protected].
  • 2 Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 3 Protein Characterization Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
  • 4 Inflammatory Cell Dynamics Section, Laboratory of Integrative Cancer Immunology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 5 Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 6 Confocal Microscopy Core Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 7 High-Dimension Data Analysis Group, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 8 Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: [email protected].
PMID: 41344331 DOI: 10.1016/j.molcel.2025.11.010
Abstract

Protein and RNA acetylation are crucial for development and Cancer progression. NAT10 is the only known acetyltransferase responsible for N4-acetylcytidine (ac4C) modification of RNA. However, the mechanism by which NAT10 contributes to Cancer progression remains unclear. Here, we show that NAT10 interacts with a mechanosensitive, metastasis-susceptibility protein complex at the nuclear pore. Loss of NAT10's acetylation activity significantly reduces lung metastasis in both allograft and genetically engineered mouse models of breast Cancer. Unexpectedly, upon NAT10 knockout, loss of ac4C modification in chromatin-associated tRNAs disrupts p300/CBP function, resulting in genome-wide chromatin reorganization and altered expression of genes that recruit metastasis-promoting myeloid cells to the tumor microenvironment. These findings highlight a role for NAT10 in regulating enhancer activity in metastatic tumor cells and reveal its impact on tumor-immune interactions that contribute to metastatic progression.

Keywords

acetylation; chromatin; enhancer; metastasis; neutrophils; tRNA; transcription; tumor microenvironment.

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