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Updated: Jan 13, 2026

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TGF-β1/SMAD signaling downregulates KLF4 expression via direct transcriptional suppression and FAT10-mediated

Zeping Chen1, Senlin Zhao2,3, Desheng Chen4,5

  • 1Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China.

Cell & Bioscience
|January 6, 2026
PubMed
Abstract

Insights

TGF-β1 signaling suppresses Krüpple-like factor 4 (KLF4) in liver cancer by upregulating FAT10. This leads to KLF4 degradation and reduced survival in hepatocellular carcinoma (HCC) patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Loss of Krüpple-like factor 4 (KLF4) tumor suppressor is linked to aggressive hepatocellular carcinoma (HCC) and poor prognosis.
  • Mechanisms driving KLF4 loss in HCC remain largely uncharacterized.

Purpose of the Study:

  • To investigate how canonical Transforming Growth Factor-beta 1 (TGF-β1) signaling suppresses KLF4 expression in HCC.
  • To elucidate the role of FAT10 in KLF4 regulation within HCC.

Main Methods:

  • Tissue microarray and immunohistochemistry to assess KLF4, FAT10, and phospho-SMAD2/3 (pSMAD2/3) expression.
  • Western blot, qPCR, ChIP, reporter assays, co-immunoprecipitation, and immunofluorescence to analyze TGF-β1 signaling impacts and protein interactions.

Main Results:

  • Elevated pSMAD2/3 correlated with increased FAT10 and decreased KLF4 in HCC, associated with reduced patient survival.
  • TGF-β1 signaling transcriptionally upregulated FAT10 and downregulated KLF4 by enhancing SMAD2/3 binding to their promoters.
  • FAT10 directly interacted with KLF4, promoting its ubiquitin-independent proteasomal degradation.

Conclusions:

  • Active TGF-β1/SMAD signaling drives KLF4 loss in HCC via FAT10-mediated proteasomal degradation.
  • TGF-β1 directly suppresses KLF4 transcription, contributing to HCC progression.
Keywords:
FAT10Hepatocellular carcinomaKLF4Proteasomal degradationTGF-β1

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