Class IIa HDACs Are Signal Responsive Deacetylases

The potent repressive activity of class IIa HDACs on MEF2 dictates that these deacetylases must be subject to strict regulation to protect skeletal muscle. Studies in cultured cells showed that all class IIa HDAC members are regulated by phosphorylation and intracellular trafficking. Phosphorylation of several conserved serine residues in the N-terminus creates docking sites for the 14-3-3 protein (Fig. 2) (Grozinger and Schreiber 2000 Wang et al. 2000). Binding of 14-3-3 to HDAC4 and -5 causes...

HDAC4 and Amyotrophic Lateral Sclerosis

ALS is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons (Robbins et al. 2010). With an incidence of 2 per 100,000 per year, this is a rare but devastating disease. Symptom onset is usually in the fifth decade, beginning with decreased fine motor control and coordination. Typically, motor strength and function continues to decline over a 3- to 5-year time course until patients succumb to death due to inability to breathe or swallow. Only 10 of the...

HDACi and Inflammatory Cells

Early studies showed that hydroxamate-based pan-HDACi compounds, such as TsA, SAHA and similar agents, have inhibitory effects on cytokine production by LPS-treated monocytes cultured in vitro (Table 1) as well as in mice injected Table 1 Effects of HDACi on cells in vitro ITF2357 (Leoni et al. 2005) Butyrate (Saemann et al. 2000), NVP-LAQ824 (Brogdon et al. 2007), TsA (Han and Lee 2009) SAHA (Leoni et al. 2002), ITF2357 (Leoni et al. 2005) SAHA (Leoni et al. 2002), ITF2357 (Leoni et al. 2005)...

Discussion and Perspective

Though many lines of evidence implicate HDACs in the regulation of tumori-genesis by deacetylation of nonhistones, there remains little direct evidence linking HDACs to cancer. Whether HDACs are primarily tumor promoters or tumor suppressors is difficult to discern. For example, SIRT1 deacetylates and deactivates some tumor suppressors, such as p53 and Rb, and thus represses apoptosis, suggesting that SIRT1 acts as a tumor promoter. The fact that SIRT1 is over-expressed in a variety of tumor...

HDACi and Foxp3 Tregs

The clinical use of many pan-HDACi is associated with a common adverse effect profile of cardiac QT prolongation, nausea, diarrhea, vomiting, hypokalemia, loss of appetite and thrombocytopenia, plus in many cases, profound and debilitating fatigue. Likewise, their ability to induce cytotoxicity is considered a key and highly desirable action in the context of malignancies, which often overexpress HDAC1 and HDAC2, but the toxicity profile and cytotoxic effects render these agents far less...

Contributors

Juliette Adjo Aka The Rosalind & Morris Goodman Cancer Research Center, McGill University, Montreal, QC, Canada H3A 1A3 Department of Medicine McGill University Health Center, McGill University, Montreal, QC, Canada H3A 1A3 Jianjun Bao Department of Pathology, Institute of Gerontology, 3015 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA Antonio Bedalov Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, abedalov fhcrc.org Richard Bedlack...

Other Signaling Pathways in Skeletal Muscle Remodeling

Peroxisome proliferator-activated receptor delta (PPAR8) and its coactivator peroxisome proliferator-activated receptor coactivator-1 alpha (PGC-1a) are key regulators of genes involved in mitochondria and oxidative metabolism in skeletal muscle. Expression of PGC-1a is higher in type I fibers. One study showed that PGC-1a mRNA levels are 5-fold higher in soleus (slow-oxidative fibers) than gastrocnemius (mixed) or EDL (fast-glycolytic fibers) muscle. Supporting an instructive role for PGC-1a...

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...

Class IIa HDAC in Neural Activity Dependent Muscle Remodeling

A connection of class IIa HDACs to neural activity was established by the observation that HDAC4 mRNA as well as protein is dramatically induced in skeletal muscle subject to surgical denervation (Cohen et al. 2007). To a lesser extent, HDAC5 is also induced whereas MITR expression is modestly repressed (Cohen et al. 2007 Mejat et al. 2005). While an extreme condition, surgical denervation has served as a useful model to investigate how skeletal muscle responds to a loss of neural input....

Specification of Myofibers

The proper specification of myofibers is essential for body movement, endurance, and metabolic regulation. Myofibers adopt their specific contractile and metabolic properties depending upon the pattern of excitation by motor neurons. These properties are best illustrated by the classical cross-innervation studies where reinnervation of slow-oxidative muscle by motor neurons normally innervating fast-glycolytic fibers are able to induce a slow-oxidative to fast-glycolytic change (Buller et al....

Conclusions

The past 10 years of research have significantly advanced our understanding of the functions and modes of regulation of HDACs in the heart. The next wave of discovery will likely focus on translating these basic, mechanistic findings into novel therapeutics for heart failure. This process would be greatly facilitated by the discovery of the pathological HDAC(s) in the heart. Genetic studies have implicated HDAC2 as a positive regulator of heart failure, but the results remain equivocal....

HDACs in Fiber Type Specification

Inactivation of HDAC genes in mouse models have been performed for all class I and class IIa HDACs. HDAC4-null mice die shortly after birth with labored breathing due to abnormal ossification of the rib cage (Vega et al. 2004), whereas HDAC5- and HDAC9-null mice are viable, but develop cardiac hypertrophy due to increased responsiveness to calcineurin-mediated MEF2 transcriptional activation (Zhang et al. 2002b Chang et al. 2004). In HDAC4, HDAC5, and HDAC9-null mouse models, there was no...

Efficacy of HDAC Inhibitors in Preclinical Models of Heart Failure

Since class IIa HDACs function as suppressors of cardiac hypertrophy, HDAC inhibitors were initially expected to promote hypertrophy. However, experiments with cultured cardiac myocytes revealed that HDAC inhibitors effectively suppress myocyte hypertrophy (Antos et al. 2003). There are at least two explanations for these seemingly paradoxical findings. First, as mentioned above, the class Ila HDAC enzymatic assay revealed that these HDACs are relatively insensitive to standard HDAC inhibitors,...

Class Iii Hdacs in the Heart

Class III HDACs (sirtuins), which are NAD+ dependent, appear to serve protective functions in the heart. SIRT1 overexpression enhances the survival of cultured neonatal rat cardiomyocytes under conditions of serum starvation (Alcendor et al. 2004). In vivo, transgenic overexpression of moderate levels of SIRT1 in mouse heart protects against cardiac apoptosis and hypertrophy in response to aging and oxidative stress (Alcendor et al. 2007). In contrast, suppression of endogenous SIRT1 activity...

The Biology of HDAC in Cancer The Nuclear and Epigenetic Components

Astrid Hagelkruys, Anna Sawicka, Magdalena Rennmayr, and Christian Seiser 1 The Role of HDAC Family Members in Development and 2 The Hallmarks of Cancer 2.1 Proliferation and Cell Cycle 3 HDAC Involvement in Specific Tumor 3.1 Hematological 3.2 Breast 3.3 Ovarian 3.4 Cancers of the Digestive 3.6 Prostate 3.7 Lung 4 Summary and Abstract Traditionally, cancer has been regarded to originate from genetic alterations such as mutations, deletions, rearrangements as well as gene amplifications,...

The Biology and Therapeutic Implications of HDACs in the Heart

2 Class Ila HDACs in the 2.1 Extranuclear Roles for Class Ila HDACs in the 2.2 Signaling to Class Ila HDACs in the 3 Class IIb HDACs in the 4 Class I HDACs in the 5 Class III HDACs in the 6 HDAC 6.1 Efficacy of HDAC Inhibitors in Preclinical Models of Heart 6.2 Translating Preclinical Findings with HDAC Inhibitors to the Abstract The heart responds to stresses such as chronic hypertension and myocardial infarction by undergoing a remodeling process that is associated with myocyte hypertrophy,...

HDACs in Skeletal Muscle Remodeling and Neuromuscular Disease

Cohen, Richard Bedlack, and Tso-Pang Yao 1 Skeletal Muscles Are Heterogeneous in Contractile and Metabolic Properties 80 2 Specification of 3 Calcium Signaling and Activity-Dependent Muscle 4 Class IIa Histone Deacetylases Are Potent Regulators of 5 Class IIa HDACs Are Signal-Responsive 6 Class IIa HDAC in Neural Activity-Dependent Muscle 7 HDACs in Fiber Type 8 HDACs in Synaptic Gene 9 HDACs in Muscle Fiber Size Control and 10 Complex Regulation of HDAC4 in Skeletal...

HDACs in Skeletal Muscle Regeneration

Skeletal muscle has the capability to regenerate, but like other tissues, its regenerative capacity is limited. Skeletal muscle regeneration and repair can be divided into three, sometimes overlapping, phases 1 inflammation, 2 tissue formation, and 3 tissue remodeling reviewed in Grefte et al. 2007 . Upon myofiber injury, damage to the plasma membrane causes a large influx of extracellular calcium, resulting in calcium-dependent proteolysis Alderton and Steinhardt 2000 . Myofiber necrosis...

Class Ila HDACs in the Heart

Cardiac hypertrophy in response to pathological stimuli has long been viewed as a compensatory mechanism that normalizes wall stress and enhances cardiac performance. However, long-term suppression of cardiac hypertrophy is associated with reduced morbidity and mortality in patients with hypertension, and thus chronic cardiac hypertrophy is now considered maladaptive Devereux et al. 2004 Gardin and Lauer 2004 . The first connection between HDACs and regulation of pathological cardiac remodeling...

HDACs and DNA Damage Repair Genome Integrity

Proper DNA repair is important for the elimination of gene mutation and maintenance of genome integrity during cell growth. Failure or abnormity of DNA repair may result in genome instability, such as deletion of tumor suppresser genes or amplification of oncogenes, and thus lead to tumorigenesis Khanna and Jackson 2001 Risinger and Groden 2004 . One of the most important functions of HDACs, besides the role of transcriptional repression, is their regulation of DNA damage responses DDR . HDAC s...

HDACs in Synaptic Gene Expression

The NMJ is a specialized synapse between the motor neuron and myofiber. As the motor axon nears the myofiber, it divides into multiple terminal boutons where vesicles filled with neurotransmitter acetylcholine ACh are released upon firing of the motor neuron. Across the synaptic cleft, the myofiber increases its surface area by developing elaborate junctional folds with a high concentration of acetylcholine receptors AChRs . This spatial concentration of AChRs at the NMJ but not other surface...

HDACs and Differentiation

Dysregulation of differentiation is a characteristic of cancer. Through histone deacetylation, HDACs regulate cell differentiation via modulation of the transcription of differentiation-associated genes Brunmeir et al. 2009 Glozak and Seto 2007 Hisahara et al. 2008 . However, only a few nonhistone proteins have been shown to be direct deacetylation substrates of HDACs in differentiation. The myogenic activator, MyoD, is a deacetylation substrate of HDAC1. MyoD plays an important role in muscle...

HDACs in Muscle Fiber Size Control and Atrophy

Chronically reduced neural activities associated with neuromuscular disease, aging and denervation can cause muscle atrophy, a condition characterized by excessive reduction in muscle size and strength. In neuromuscular diseases, such as amyo-trophic lateral sclerosis ALS , motor neuron dysfunction leads to severe muscle atrophy in both diaphragm and limb muscles, contributing to breathing and mobility problems, and eventual death. The muscle atrophy program employs two ubiquitin E3 ligases,...

Bromodomains PHD Fingers and Potentially Others for AcK Recognition

Acetylation affects protein function through various mechanisms, with one of them being recognition by protein domains such as the bromodomain. It has been well established that the bromodomain of GCN5, TAF250, or p300 forms an a-helix bundle containing a specific pocket for recognition of a specific AcK residue Sanchez and Zhou 2009 . The binding affinity is relatively weak but provides an opportunity to cooperate with other protein modules. For example, TRIM24 tripartite motif-containing 24,...

References

Ago T, Liu T, Zhai P, Chen W, Li H, Molkentin JD, Vatner SF, Sadoshima J 2008 A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy. Cell 133 978-993 Alcendor RR, Kirshenbaum LA, Imai S, Vatner SF, Sadoshima J 2004 Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ Res 95 971-980 Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, Tian B, Wagner T, Vatner...

Targeting Class IIb HDACs

Localized primarily to the cytoplasm, HDAC6 not only regulates the acetylation of multiple proteins, such as a-tubulin and heat shock protein 90 HSP90 , but also has deacetylase-independent functions Grozinger et al. 1999 Hubbert et al. 2002 Kovacs et al. 2005 Bali et al. 2005 Valenzuela-Fernandez et al. 2008 . Unique in the field of HDACi, multiple HDAC6 isoform-selective HDACi HDAC6i are reported Haggarty et al. 2003 Suzuki et al. 2006 Schafer et al. 2008 Chen et al. 2008 Kozikowski et al....