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Histone modifications affect differential regulation of TGFβ- induced NADPH oxidase 4 (NOX4) by wild-type and mutant

Howard E Boudreau1, Wei Feng Ma1, Agnieszka Korzeniowska1

  • 1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Oncotarget
|June 3, 2017
PubMed

Insights

Mutant p53 proteins enhance NADPH oxidase-4 (NOX4) expression and tumor cell migration, while wild-type p53 suppresses it. This involves epigenetic regulation of NOX4, suggesting NOX4 as a therapeutic target.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Wild-type (WT) p53 suppresses reactive oxygen species (ROS) and cell migration, whereas mutant (mut) p53 enhances them.
  • NADPH oxidase-4 (NOX4) is implicated in tumor progression and metastasis.
  • Transforming growth factor-beta (TGFβ) signaling plays a role in cancer development.

Purpose of the Study:

  • To investigate the role of p53 and SMAD3 in the transcriptional regulation of NOX4.
  • To explore the epigenetic mechanisms underlying NOX4 induction by mutant p53.
  • To identify NOX4 as a potential therapeutic target for cancer treatment.

Main Methods:

  • Analysis of The Cancer Genome Atlas (TCGA) data for correlations between p53 mutations and NOX4 expression.
  • Cell culture experiments to study the effects of p53 levels on NOX4 expression.
  • Chromatin immunoprecipitation (ChIP) assays to examine protein-DNA interactions.
  • Histone acetylation analysis of the NOX4 promoter.
  • Wound healing assays to assess cell migration.

Main Results:

  • Mutant p53 correlates with increased NOX4 expression in tumors.
  • Mutant p53 supports TGFβ/SMAD3-dependent NOX4 expression via specific SMAD3 binding elements (SBEs).
  • Wild-type p53 suppresses NOX4 transcription, an effect reversed by transactivation domain mutation or HDAC inhibitors.
  • p300 (a histone acetyltransferase) enhances NOX4 induction, and mutant p53 augments TGFβ-stimulated histone acetylation in the NOX4 promoter.
  • NOX4 and p300 promote TGFβ/mutant p53-mediated cell migration.

Conclusions:

  • Mutant p53, SMAD3, and epigenetic modifications converge to induce NOX4 expression, promoting tumor cell migration.
  • NOX4 is a key mediator in the TGFβ/mutant p53 signaling pathway.
  • Targeting NOX4 may offer a therapeutic strategy against cancer progression and metastasis.
Keywords:
NOX4cell migrationhistone modificationmutant p53p300

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