Class IIa HDACs as Therapeutic Targets

MITR potently inhibits MEF2 transcription activity despite lacking the catalytic deacetylase domain [Fig. 2, Zhang et al. (2001b)]. The deacetylase-independent repression by class IIa HDACs is further bolstered by findings that mutations in conserved residues in the catalytic domain have little effect on the ability of HDAC4 to repress MEF2 (Wang et al. 1999). Therefore, the deacetylase domain of class IIa HDACs is not essential for their transcriptional repressive activity toward MEF2. This begs a critical question: is there a function for the conserved catalytic domain in class IIa HDAC?

Although it is logical to propose that the HDAC4 catalytic domain acts to deacetylate specific substrates, as discussed previously, evidence indicates that deacetylase activity of ectopically expressed HDAC4 was conferred by associated HDAC3 (Fischle et al. 2002). Sequence analysis of the catalytic domain of vertebrate HDAC4 and other class IIa HDACs reveals that a conserved tyrosine in the catalytic center is replaced by histidine (Lahm et al. 2007). The crystal structure of HDAC4 deacetylase domain demonstrates that this substitution results in a loss of critical contact with acetylated substrate for deacetylation (Bottomley et al. 2008). Indeed, conversion of this histidine to tyrosine restores the histone deacetylase activity (Lahm et al. 2007). These findings support the proposition that HDAC4 and related class IIa deacetylases do not possess intrinsic deacetylase activity. This would pose a challenge to inhibit HDAC4 directly via classical HDAC inhibitors. If HDAC4 indeed exerts its deacetylase function via HDAC3, it is possible to inhibit HDAC4 through many available HDAC inhibitors that target HDAC3. It also remains possible that specific protein-protein interactions or protein modifications could activate the cryptic deacetylase domain of IIa HDACs. Alternatively, the deacetylase domain of HDAC4 was proposed to serve as a acetylated lysine binding module, an activity analogous to the BROMO domain (Bradner et al. 2010). One potential clue to the importance of the deacetylase domain came from a mutant mouse strain whose HDAC4 is disrupted by insertional mutagenesis, resulting in a truncated HDAC4 with intact MEF2 binding domain but lacking the C-terminus catalytic domain. In contrast to the HDAC4 null mutant mice, which show severe skeletal defect and die within a few days after birth (Vega et al. 2004), this HDAC4 mutant (ACAT) strain is viable and grossly normal (Rajan et al. 2009). These phenotypes are consistent with findings that dysregulation of MEF2 is responsible for the skeletal defect observed in HDAC4 KO mice (Vega et al. 2004). Nonetheless, these mice show reduced thermal nociception and seizures, suggesting that the catalytic domain of HDAC4, independent of MEF2, regulates pain signaling and neural function. The intact catalytic domain of HDAC4 is also required for the regulation of muscle atrophy caused by denervation (MCC, TJC, TPY, unpublished results). Therefore, the conserved deacetylase domain in HDAC4 has a unique function and might be targeted pharmacologically.

Given the prominent role for HDAC4 in muscle atrophy and reinnervation, the development of inhibitors for HDAC4 could prove to be effective in the treatment of ALS and related motor neuron disease. The utility of broad-spectrum HDACIs has been tested in ALS mouse and rat models. Valproic acid (VPA), an anticonvulsant used in the treatment of epilepsy and mood disorders, is known to have HDACI activity. In one study, preonset treatment of ALS mice with VPA resulted in prolongation of life span, while VPA treatment after disease onset had no effect (Sugai et al. 2004). In a similar study, preonset treatment of ALS mice with VPA displayed a delay on symptom onset, but no effect on life span (Rouaux et al. 2007). VPA has also been shown to enhance motor function and peripheral nerve regeneration following nerve injury in a rat model (Cui et al. 2003). Analogously, treatment with another HDACI, phenylbutyrate (NaBP), yielded similar results. Treatment of ALS mice with NaBP led to prolonged survival (22%) and improved ALS phenotype (Ryu et al. 2005; Petri et al. 2006). Both VPA and NaBP are relatively weak HDAC inhibitors. Vorinostat (SAHA) is a more potent pan-HDAC inhibitor, which has been approved for cutaneous T-cell lymphoma treatment (Marks 2007). Its utility on ALS therapy is not known. Nevertheless, pan HDACI treatment could, in theory, have some adverse effects, as it could affect important processes controlled by other HDAC members. Ideally, the development of HDAC4-selective inhibitors could potentially offer more efficacious agents for treating ALS and other related neuromuscular diseases.

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