View the Current Issue

Article

  • The EMBO Journal (2003) 22, 3411 - 3420
  • doi:10.1093/emboj/cdg315

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

Oliver H. Krämer1,5, Ping Zhu2,5, Heather P. Ostendorff3, Martin Golebiewski2, Jens Tiefenbach1, Marvin A. Peters3, Boris Brill1, Bernd Groner1, Ingolf Bach3, Thorsten Heinzel1 and Martin Göttlicher2,4

  1. Georg-Speyer-Haus, Paul-Ehrlich-Stras zlige 42-44, D-60596 Frankfurt, Germany
  2. Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, H.-v.-H.-Platz 1, D-76344 Eggenstein Germany
  3. Zentrum für Molekulare Neurobiologie (ZMNH), Universität Hamburg, Martinistras zlige 85, D-20251 Hamburg, Germany
  4. Present address: GSF National Research Center on Environment and Health, Institute of Toxicology, Ingolstädter Landstras zlige 1, D-85754 Neuherberg, Germany
  5. O.H.Krämer and P.Zhu contributed equally to this work

Correspondence to:

Thorsten Heinzel, E-mail: heinzel@em.uni-frankfurt.de

Martin Göttlicher, E-mail: martin.goettlicher@gsf.de

Received 26 November 2002; Accepted 8 May 2003; Revised 17 April 2003

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.

  • Keywords:

    • HDAC2,
    • HDAC inhibitor,
    • histone deacetylase,
    • proteasomal degradation,
    • valproic acid