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Assays for Validating Histone Acetyltransferase Inhibitors
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Assays for Validating Histone Acetyltransferase Inhibitors

Published on: August 6, 2020

Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c-Myc collaborating genes

Marinus R Heideman1, Roel H Wilting, Eva Yanover

  • 1Division of Gene Regulation, Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands.

Blood
|January 19, 2013
PubMed

Insights

Gradual loss of histone deacetylase (HDAC) activity in mice promotes thymic lymphoma development by impairing a p53-dependent barrier. Tumor cells, however, remain dependent on HDAC activity for survival.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Immunology

Background:

  • Histone deacetylases (HDACs) are crucial epigenetic regulators involved in gene expression.
  • HDAC inhibitors (HDACi) are explored as cancer therapeutics, with approved use in hematological malignancies.
  • Understanding in vivo HDAC function is vital for therapeutic development.

Purpose of the Study:

  • To investigate the role of Hdac1 and Hdac2 in thymocyte development and lymphomagenesis.
  • To elucidate the mechanisms by which HDAC activity influences oncogenic transformation in the thymus.
  • To determine the therapeutic potential of targeting HDACs in thymic lymphomas.

Main Methods:

  • Generation of compound conditional knockout mice for Hdac1 and Hdac2 to create a thymocyte-specific gradient of HDAC activity.
  • Genomic, biochemical, and functional analyses of pre-leukemic thymocytes and tumors.
  • Assessment of lymphoma incidence, latency, and developmental blocks.

Main Results:

  • Dosage-dependent accumulation of immature thymocytes and increased incidence/latency of thymic lymphomas upon gradual HDAC activity loss.
  • Complete ablation of Hdac1/Hdac2 abrogated lymphomagenesis due to a block in early thymic development.
  • HDAC activity regulates a p53-dependent barrier against Myc-driven lymphomagenesis, involving genes like Jdp2.

Conclusions:

  • Hdac1/Hdac2-governed HDAC activity is critical for maintaining a p53-dependent barrier against thymic lymphoma formation.
  • Reduced HDAC activity facilitates initial oncogenic transformation but resulting tumors remain dependent on HDAC activity for maintenance.
  • Targeting HDACs may offer therapeutic strategies, but careful consideration of dosage is needed due to dual roles in transformation and maintenance.

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