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DUSP12 Regulates NAT10-Mediated RNA Acetylation to Modulate DNA Repair and Therapeutic Response in Hepatocellular

Viktor Kalbermatter Boell1, Diana Reis Della Corte Guimarães Pacheco1, Yuli Thamires Magalhães1

  • 1Department of Biochemistry Institute of Chemistry University of São Paulo (USP) São Paulo Brazil.

Medcomm
|August 19, 2026
PubMed

Insights

Dual-specificity phosphatase 12 (DUSP12) and its interaction with N-acetyltransferase 10 (NAT10) were studied in liver cancer. DUSP12 loss enhances chemotherapy sensitivity by impacting DNA damage and RNA acetylation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Hepatocellular carcinoma (HCC) is an aggressive liver cancer with limited therapeutic options.
  • Chemotherapy remains a key treatment modality for HCC.
  • Understanding molecular mechanisms driving HCC progression and treatment resistance is crucial.

Purpose of the Study:

  • To investigate the role of dual-specificity phosphatase 12 (DUSP12) in HCC.
  • To explore the interaction between DUSP12 and nucleolar protein N-acetyltransferase 10 (NAT10) under genotoxic stress.
  • To identify potential therapeutic vulnerabilities in HCC.

Main Methods:

  • Utilized CRISPR-Cas9 to create DUSP12 knockout HCC models.
  • Administered genotoxic agents (doxorubicin, cisplatin) and Remodelin.
  • Performed DNA damage response assays (γH2AX, p53), protein interaction studies, and RNA modification analysis (ac4C).
  • Analyzed DUSP12 amplification and expression in HCC patient data.

Main Results:

  • Doxorubicin induced greater cytotoxicity than cisplatin, linked to DNA damage response (DDR) and nucleolar stress.
  • DUSP12 knockout sensitized HCC cells to doxorubicin, impairing DNA repair and altering NAT10 localization.
  • DUSP12 interacts with NAT10, and DUSP12 deletion affects NAT10 activity and N4-acetylcytidine (ac4C) RNA modification.
  • HCC patients with DUSP12 amplification or high expression showed poor survival and enriched DDR/ribosome biogenesis pathways.

Conclusions:

  • The DUSP12-NAT10 axis is a novel link between DDR and nucleolar stress in HCC.
  • DUSP12 loss represents a potential therapeutic vulnerability in liver cancer.
  • Targeting the DUSP12-NAT10-ac4C pathway could offer new treatment strategies for HCC.
Keywords:
N4‐acetylcytidine (ac4C)N‐acetyltransferase 10 (NAT10)doxorubicindual‐specificity phosphatase 12 (DUSP12)hepatocellular carcinoma (HCC)nucleolar stress

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