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TAp73 protein stability is controlled by histone deacetylase 1 via regulation of Hsp90 chaperone function

Jin Zhang1, Enshun Xu1, Xinbin Chen1

  • 1Comparative Oncology Laboratory, University of California at Davis, Davis, California 95616.

The Journal of Biological Chemistry
|January 31, 2013
PubMed

Insights

Histone deacetylase 1 (HDAC1) regulates TAp73 protein stability via the HSP90 complex. HDAC1 inhibition decreases TAp73, impacting cell migration and suggesting TAp73 as a mediator of HDAC1-driven cancer cell movement.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • Histone deacetylases (HDACs) are crucial in cellular processes, with HDAC inhibitors showing therapeutic potential in cancer.
  • The p53 family member p73 is vital for tumor suppression and neural development, producing antagonistic isoforms TAp73 and ΔNp73.
  • Understanding the regulation of p73 by HDACs is key to developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the role of HDACs in regulating p73 protein stability.
  • To elucidate the molecular mechanisms underlying HDAC-mediated regulation of TAp73.
  • To determine the functional consequences of altered TAp73 stability in cellular processes like migration.

Main Methods:

  • Utilized HDAC inhibitors and siRNA to modulate HDAC1 activity.
  • Assessed TAp73 protein half-life and expression levels under various conditions.
  • Investigated the interaction between HDAC1, HSP90, and TAp73 using biochemical assays.
  • Analyzed cell migration in response to HDAC1 knockdown.

Main Results:

  • HDAC1 inhibition or knockdown led to decreased TAp73 protein stability and expression.
  • HDAC1 knockdown caused hyperacetylation and inactivation of HSP90, disrupting the HSP90-TAp73 interaction.
  • This disruption promoted TAp73 proteasomal degradation.
  • Down-regulation of TAp73 was essential for the enhanced cell migration observed upon HDAC1 knockdown.

Conclusions:

  • HDAC1 is a critical regulator of TAp73 protein stability through the HSP90 chaperone complex.
  • HDAC1 influences TAp73 stability via post-translational modification (acetylation) of HSP90.
  • TAp73 acts as a downstream mediator of HDAC1-regulated cell migration, highlighting a novel therapeutic target in cancer.

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