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Tumor suppressor SMAR1 downregulates Cytokeratin 8 expression by displacing p53 from its cognate site

Lakshminarasimhan Pavithra1, Sandeep Singh, Kadreppa Sreenath

  • 1National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune 411007, India.

The International Journal of Biochemistry & Cell Biology
|September 30, 2008
PubMed

Insights

Tumor suppressor SMAR1 downregulates Cytokeratin 8, a key intermediate filament, by modulating p53. This reduces cancer cell migration and invasiveness, with inverse SMAR1/Cytokeratin 8 expression in advanced breast cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Intermediate filaments are crucial in malignant cell transformation.
  • Cytokeratin 8 (KRT8) is implicated in cancer progression.
  • Tumor suppressor proteins regulate cellular phenotypes.

Purpose of the Study:

  • To elucidate the regulatory mechanism of Cytokeratin 8 gene expression by the tumor suppressor SMAR1.
  • To investigate the role of SMAR1-mediated downregulation of Cytokeratin 8 in cancer cell behavior.
  • To analyze the expression patterns of SMAR1 and Cytokeratin 8 in breast cancer tissues.

Main Methods:

  • Investigated SMAR1's effect on p53-mediated transactivation of the Cytokeratin 8 gene.
  • Utilized genotoxic stress agents to modulate SMAR1 protein levels.
  • Analyzed gene transcription via chromatin condensation, histone methylation, and deacetylation.
  • Evaluated SMAR1 and Cytokeratin 8 protein expression in breast cancer tissue microarrays.

Main Results:

  • SMAR1 downregulates Cytokeratin 8 gene expression by modulating p53.
  • Reduced cell surface cytokeratin expression led to decreased cell migration and invasiveness.
  • Genotoxic stress increased SMAR1, repressing Cytokeratin 8 transcription through chromatin modification.
  • Higher grades of breast cancer showed inverse expression: low SMAR1 and high Cytokeratin 8.

Conclusions:

  • SMAR1, in conjunction with p53, provides a mechanism for regulating Cytokeratin 8.
  • SMAR1-mediated suppression of Cytokeratin 8 impacts cancer cell malignancy.
  • The inverse correlation in breast cancer highlights the potential role of the SMAR1-Cytokeratin 8 axis in tumor progression.

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