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Histone deacetylase inhibitors upregulate Rap1GAP and inhibit Rap activity in thyroid tumor cells

Xiaoyun Dong1, Christopher Korch, Judy L Meinkoth

  • 1Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, 19104 Pennsylvania, USA.

Endocrine-Related Cancer
|March 4, 2011
PubMed

Insights

Histone deacetylase (HDAC) inhibitors can restore Rap1GAP expression in thyroid cancer cells, potentially impairing Rap activity. This suggests HDAC inhibitors may offer a new therapeutic strategy for thyroid tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Increased Rap activity is linked to tumor progression.
  • Downregulation of Rap1GAP occurs frequently in human tumors, including thyroid carcinomas.
  • Restoring Rap1GAP expression could be a therapeutic strategy.

Purpose of the Study:

  • To investigate the restoration of endogenous Rap1GAP expression in thyroid tumor cells.
  • To evaluate the effects of deacetylase inhibitors and a demethylating agent on Rap1GAP expression.
  • To examine the impact of these treatments on Rap2 activity in thyroid cancer.

Main Methods:

  • Treatment of differentiated and anaplastic thyroid carcinoma (ATC) cell lines with HDAC inhibitors (sodium butyrate, trichostatin A) and a demethylating agent (5-aza-deoxycytidine).
  • Western blotting to assess Rap2 expression and activity.
  • Analysis of Rap1GAP expression levels following treatment.

Main Results:

  • HDAC inhibitors increased Rap1GAP expression in differentiated thyroid carcinoma cell lines and some ATC cell lines.
  • The demethylating agent restored Rap1GAP in one ATC cell line and enhanced HDAC inhibitor effects in another.
  • HDAC inhibitors impaired Rap2 activity in both differentiated and anaplastic thyroid tumor cells.
  • Rap2 was highly expressed in human thyroid cancer cells.

Conclusions:

  • HDAC inhibitors can restore Rap1GAP expression and impair Rap activity in thyroid tumor cells.
  • Epigenetic modifications, including histone deacetylation and demethylation, influence Rap regulators.
  • HDAC inhibitors represent a potential therapeutic approach for targeting Rap activity in human tumors.

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