The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2.
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.
Krämer
Oliver H
OH
Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, D-60596 Frankfurt, Germany.
Zhu
Ping
P
Ostendorff
Heather P
HP
Golebiewski
Martin
M
Tiefenbach
Jens
J
Peters
Marvin A
MA
Brill
Boris
B
Groner
Bernd
B
Bach
Ingolf
I
Heinzel
Thorsten
T
Göttlicher
Martin
M
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006868:Hydrolysis; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D025801:Ubiquitin / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
D017931:DNA Primers; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009097:Multienzyme Complexes; D025801:Ubiquitin; C012589:trichostatin A; D014635:Valproic Acid; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex