1. Academic Validation
  2. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases

A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases

  • Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3003-7. doi: 10.1073/pnas.95.6.3003.
V M Richon 1 S Emiliani E Verdin Y Webb R Breslow R A Rifkind P A Marks
Affiliations

Affiliation

  • 1 Cell Biology Program, Memorial Sloan-Kettering Cancer Center 1275 York Avenue, New York, NY 10021, USA. v-richon@ski.mskcc.org
Abstract

Hybrid polar compounds (HPCs) have been synthesized that induce terminal differentiation and/or Apoptosis in various transformed cells. We have previously reported on the development of the second-generation HPCs suberoylanilide hydroxamic acid (SAHA) and m-carboxycinnamic acid bishydroxamide (CBHA) that are 2,000-fold more potent inducers on a molar basis than the prototype HPC hexamethylene bisacetamide (HMBA). Herein we report that CBHA and SAHA inhibit histone deacetylase 1 (HDAC1) and histone deacetylase 3 (HDAC3) activity in vitro. Treatment of cells in culture with SAHA results in a marked hyperacetylation of histone H4, but culture with HMBA does not. Murine erythroleukemia cells developed for resistance to SAHA are cross-resistant to trichostatin A, a known deacetylase inhibitor and differentiation inducer, but are not cross-resistant to HMBA. These studies show that the second-generation HPCs, unlike HMBA, are potent inhibitors of HDAC activity. In this sense, HMBA and the second-generation HPCs appear to induce differentiation by different pathways.

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