Cloning and characterization of a novel human histone deacetylase, HDAC8

Abstract

Histone deacetylases (HDACs) are a growing family of enzymes implicated in transcriptional regulation by affecting the acetylation state of core histones in the nucleus of cells. HDACs are known to have key roles in the regulation of cell proliferation [Brehm, Miska, McCance, Reid, Bannister and Kouzarides (1998) Nature (London) 391, 597-600], and aberrant recruitment of an HDAC complex has been shown to be a key step in the mechanism of cell transformation in acute promyelocytic leukaemia [Grignani, De Matteis, Nervi, Tomassoni, Gelmetti, Cioce, Fanelli, Ruthardt, Ferrara, Zamir et al. (1998) Nature (London) 391, 815-818; Lin, Nagy, Inoue, Shao, Miller and Evans (1998), Nature (London) 391, 811-814]. Here we present the complete nucleotide sequence of a cDNA clone, termed HDAC8, that encodes a protein product with similarity to the RPD3 class (I) of HDACs. The predicted 377-residue HDAC8 product contains a shorter C-terminal extension relative to other members of its class. After expression in two cell systems, immunopurified HDAC8 is shown to possess trichostatin A- and sodium butyrate-inhibitable HDAC activity on histone H4 peptide substrates as well as on core histones. Expression profiling reveals the expression of HDAC8 to various degrees in every tissue tested and also in several tumour lines. Mutation of two adjacent histidine residues within the predicted active site severely decreases activity, confirming these residues as important for HDAC8 enzyme activity. Finally, linkage analysis after radiation hybrid mapping has localized HDAC8 to chromosomal position Xq21.2-Xq21.3. These results confirm HDAC8 as a new member of the HDAC family.

Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen

“…4A), which is within the therapeutic range for VPA therapy in humans. To test whether VPA inhibits HDACs other than HDAC1, we prepared nuclear extracts from HeLa cells, which express multiple HDACs, including HDAC1, 2, 3, 4, and 8 (36,44,45), 2 and assayed HDAC activity as above in the presence of VPA (Fig. 4B).…”

HDAC3: taking the SMRT-N-CoRrect road to repression

“…This similarity led to the classification of the above three proteins into one family. HDAC8 would be later added to this class, which includes mammalian enzymes related to yeast Rpd3 (Buggy et al, 2000). Similar to HDACs 1 and 2, HDAC3 is also ubiquitously expressed.…”

CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo

“…The acetylation state of histones is maintained by the opposing actions of histone acetyl transferase enzymes and histone deacetylases (HDAC). There are 11 known isoforms of the classic HDAC family, denoted HDAC1 to HDAC11 (1,2). In addition to histones, HDAC enzymes are known to deacetylate other proteins, including a-tubulin (3), suggesting complex, multifunctional roles for HDACs in vivo.…”