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The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2

Oliver H. Krämer, Ping Zhu, Heather P. Ostendorff, Martin Golebiewski, Jens Tiefenbach, Marvin A. Peters, Boris Brill, Bernd Groner, Ingolf Bach, Thorsten Heinzel, Martin Göttlicher

Author Affiliations

  1. Oliver H. Krämer1,4,
  2. Ping Zhu2,4,
  3. Heather P. Ostendorff3,
  4. Martin Golebiewski2,
  5. Jens Tiefenbach1,
  6. Marvin A. Peters3,
  7. Boris Brill1,
  8. Bernd Groner1,
  9. Ingolf Bach3,
  10. Thorsten Heinzel*,1 and
  11. Martin Göttlicher*,2,4
  1. 1 Georg‐Speyer‐Haus, Paul‐Ehrlich‐Straße 42‐44, D‐60596, Frankfurt, Germany
  2. 2 Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, H.‐v.‐H.‐Platz 1, D‐76344, Eggenstein, Germany
  3. 3 Zentrum für Molekulare Neurobiologie (ZMNH), Universität Hamburg, Martinistraße 85, D‐20251, Hamburg, Germany
  4. 4 Present address: GSF National Research Center on Environment and Health, Institute of Toxicology, Ingolstädter Landstraße 1, D‐85754, Neuherberg, Germany
  1. *Corresponding authors. E-mail: heinzel{at}em.uni-frankfurt.de or E-mail: martin.goettlicher{at}gsf.de
  1. O.H.Krämer and P.Zhu contributed equally to this work

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Abstract

Histone‐modifying enzymes play essential roles in physiological and aberrant gene regulation. Since histone deacetylases (HDACs) are promising targets of cancer therapy, it is important to understand the mechanisms of HDAC regulation. Selective modulators of HDAC isoenzymes could serve as efficient and well‐tolerated drugs. We show that HDAC2 undergoes basal turnover by the ubiquitin–proteasome pathway. Valproic acid (VPA), in addition to selectively inhibiting the catalytic activity of class I HDACs, induces proteasomal degradation of HDAC2, in contrast to other inhibitors such as trichostatin A (TSA). Basal and VPA‐induced HDAC2 turnover critically depend on the E2 ubiquitin conjugase Ubc8 and the E3 ubiquitin ligase RLIM. Ubc8 gene expression is induced by both VPA and TSA, whereas only TSA simultaneously reduces RLIM protein levels and therefore fails to induce HDAC2 degradation. Thus, poly‐ubiquitination and proteasomal degradation provide an isoenzyme‐selective mechanism for downregulation of HDAC2.

  • Received November 26, 2002.
  • Revision received April 17, 2003.
  • Accepted May 8, 2003.
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