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YBX1 Promotes Malignant Progression of HNSCC via Stabilizing NSUN2-m5C Modified ATF4 mRNA

Yanwei Li1,2, Shuang Li2, Yang Li2

  • 1Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China.

Cancer Science
|July 10, 2026
PubMed

Insights

Y-box binding protein 1 (YBX1) acts as a key reader of 5-methylcytosine (m5C) modifications, cooperating with NSUN2 to stabilize oncogenic mRNAs and drive head and neck squamous cell carcinoma (HNSCC) progression. Inhibiting both YBX1 and NSUN2 may offer a new HNSCC therapeutic strategy.

Area of Science:

  • Epitranscriptomics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Head and neck squamous cell carcinoma (HNSCC) presents significant therapeutic challenges due to aggressive metastasis and limited targeted treatments.
  • Understanding the molecular mechanisms driving HNSCC progression is crucial for developing effective therapies.

Purpose of the Study:

  • To identify novel molecular players and pathways involved in HNSCC malignant progression.
  • To investigate the role of Y-box binding protein 1 (YBX1) and its interaction with 5-methylcytosine (m5C) modifications in HNSCC.

Main Methods:

  • Integrated analysis of The Cancer Genome Atlas (TCGA) datasets for YBX1 expression in HNSCC.
  • Clinical validation of YBX1 expression as a prognostic marker in a patient cohort.
  • In vitro and in vivo functional assays to assess the impact of YBX1 modulation on HNSCC cell behavior.
  • m5C-MeRIP-seq and YBX1-RIP-seq to identify direct YBX1 targets and m5C-modified transcripts.
  • Luciferase reporter assays to confirm YBX1-m5C-mRNA interactions.

Main Results:

  • YBX1 is significantly upregulated in HNSCC and associated with poor overall survival.
  • YBX1 depletion suppresses HNSCC proliferation, migration, and invasion; YBX1 overexpression enhances these phenotypes.
  • YBX1 directly binds to m5C-modified ATF4 mRNA, stabilizing its transcripts in an NSUN2-dependent manner.
  • This interaction enhances oncogenic mRNA stability and promotes tumor progression.

Conclusions:

  • YBX1 functions as a critical m5C reader, cooperating with NSUN2 to promote HNSCC progression via mRNA stabilization.
  • The YBX1-NSUN2-m5C-ATF4 regulatory axis represents a novel epitranscriptomic pathway in HNSCC.
  • Dual inhibition of YBX1 and NSUN2 is a promising therapeutic strategy for HNSCC.
Keywords:
ATF4HNSCCNSUN2YBX1m5C methylation

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