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POU4F1 enhances lung cancer gemcitabine resistance by regulating METTL3-dependent TWF1 mRNA N6 adenosine methylation

Jianfeng Tang1, Zhijian Liu1, Guanghui Xie1

  • 1Department of Cardiovascular Thoracic Surgery, The Central Hospital of Yongzhou, No. 396 Yiyun Road, Lengshuitan District, Yongzhou, 425100 Hunan People's Republic of China.

3 Biotech
|December 16, 2024
PubMed

Insights

POU Class 4 Homeobox 1 (POU4F1) promotes gemcitabine resistance in lung cancer by increasing autophagy via METTL3-mediated TWF1 m6A modification. Reducing POU4F1 enhances anti-tumor sensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Gemcitabine (GEM) is a key chemotherapy drug for lung cancer.
  • Acquired resistance to GEM significantly limits treatment efficacy.
  • Understanding resistance mechanisms is crucial for improving lung cancer therapy.

Purpose of the Study:

  • To investigate the role of POU Class 4 Homeobox 1 (POU4F1) in regulating GEM resistance in lung cancer.
  • To elucidate the molecular mechanism by which POU4F1 influences GEM resistance.

Main Methods:

  • Gene expression analysis (RT-qPCR, Western Blot, Immunofluorescence, Immunohistochemistry).
  • Cellular assays for viability, proliferation, and apoptosis (CCK-8, EdU, TUNEL, Flow Cytometry).
  • Molecular interaction studies (MeRIP, Dual Luciferase Reporter, ChIP, RIP assays).
  • In vivo anti-tumor sensitivity assessment.

Main Results:

  • POU4F1 knockdown significantly inhibited GEM resistance and autophagy in lung cancer cells.
  • POU4F1 transcriptionally activated METTL3, which in turn promoted TWF1 m6A modification and expression.
  • Overexpression of METTL3 or TWF1 counteracted the effects of POU4F1 knockdown.
  • POU4F1 knockdown enhanced GEM anti-tumor efficacy in vivo.

Conclusions:

  • POU4F1 upregulation drives GEM resistance in lung cancer by promoting autophagy.
  • This process involves the METTL3-mediated N6-methyladenosine (m6A) modification of TWF1.
  • Targeting the POU4F1/METTL3/TWF1 axis may offer a therapeutic strategy against GEM-resistant lung cancer.
Keywords:
Gemcitabine resistanceLung cancerMETTL3POU4F1TWF1

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