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ZC3H13-mediated m6A stabilization of CCND1 promotes malignant progression and is associated with poor anti-PD-1

Wenqing Chen1, Yun Li1, Shuang Chen2

  • 1Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Clinical and Translational Medicine
|July 27, 2026
PubMed
Abstract

Insights

ZC3H13 promotes head and neck squamous cell carcinoma (HNSCC) progression and resistance to anti-programmed cell death protein 1 (anti-PD-1) therapy by stabilizing cyclin D1 mRNA. Targeting ZC3H13 may improve anti-PD-1 treatment efficacy in HNSCC.

Area of Science:

  • Oncology
  • Immunotherapy
  • Molecular Biology

Background:

  • Immune checkpoint blockade resistance limits anti-PD-1 therapy efficacy in head and neck squamous cell carcinoma (HNSCC).
  • The role of ZC3H13, an N6-methyladenosine writer complex component, in HNSCC progression and anti-PD-1 response is unknown.

Purpose of the Study:

  • To investigate the role of ZC3H13 in HNSCC progression.
  • To determine ZC3H13's impact on anti-PD-1 therapy response in HNSCC.
  • To elucidate the molecular mechanism underlying ZC3H13's function in HNSCC.

Main Methods:

  • Analysis of ZC3H13 expression in HNSCC clinical cohorts and public datasets.
  • In vitro gain- and loss-of-function studies in HNSCC cells.
  • In vivo studies using an epithelial-specific ZC3H13 conditional knockout mouse model.
  • Investigation of N6-methyladenosine modification, RNA stability, and functional rescue assays.

Main Results:

  • ZC3H13 is upregulated in HNSCC, correlating with poor prognosis and reduced anti-PD-1 response.
  • ZC3H13 promotes HNSCC cell proliferation and invasion.
  • Ablation of ZC3H13 suppresses tumor development and enhances anti-PD-1 efficacy.
  • ZC3H13 stabilizes cyclin D1 (CCND1) mRNA via N6-methyladenosine modification and IGF2BP1 interaction, driving malignant phenotypes and immunosuppressive features.

Conclusions:

  • The ZC3H13/IGF2BP1/CCND1 axis drives HNSCC progression and anti-PD-1 resistance.
  • ZC3H13 represents a potential therapeutic target to enhance anti-PD-1 treatment efficacy in HNSCC.
Keywords:
CCND1ZC3H13immunotherapy resistancem6A modification

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