Histone deacetylase (HDAC) 6 is the best-characterized class IIb deacetylase that regulates many important biological processes via the formation of complexes with its partner proteins. HDAC6 is important both for cytoplasmic and nuclear functions. Unlike other deacetylases, HDAC6 has unique substrate specificity for nonhistone proteins. Such diverse functions of HDAC6 suggest that it serves a potential therapeutic target for the treatment of a wide range of diseases. This therapeutic interest in HDAC6 stems from the observation that HDAC6 may be overexpressed or deregulated in various cancers, neurodegenerative diseases and inflammatory disorders. Despite extensive efforts, however, very few HDAC6-selective inhibitors have been identified and the precise structural determinants remain undefined. Future efforts aiming to better define the structure and function of HDAC6 should provide the basis for the discovery of novel effective inhibitors. In this review, we focus on recent studies that highlight the importance of HDAC6-mediated biological processes, disease mechanisms and HDAC6-selective inhibitors.

Accumulation of lipids inside the cell is primarily caused by disorders of lipid metabolism. S-adenosylmethionine synthetase (SAMS) produces SAM, an important methyl donor in various phospholipid methyltransferase reactions catalysed by phosphoethanolamine N-methyltransferase (PMT-1). A gel-based, quantitative proteomic analysis of the RNA interference (RNAi)-mediated inactivation of the pod-2 gene, which encodes acetyl-CoA carboxylase, showed a substantial down-regulation of SAMS-1. Consequently, RNAi of either sams-1 or pmt-1 caused a significant increase in lipid droplet size in the intestine of Caenorhabditis elegans. Lipid droplets exhibited increased triacylglycerol (TG) and decreased phosphatidylcholine (PC) levels, suggesting a reciprocal relationship between TG and PC regulation. These lipid-associated phenotypes were rescued by choline feeding. Among the five fat metabolism-related genes examined, two genes were highly induced by inactivation of sams-1 or pmt-1: pod-2 and stearoyl-CoA desaturase (fat-7). Thus, both SAMS-1 and PMT-1 were shown to contribute to the homoeostasis of TG and PC levels in C. elegans, which would provide an important survival strategy under harsh environmental conditions.

Caenorhabditis elegans undergoes a developmental molting process that involves a coordinated interplay among diverse intracellular pathways. Here, we investigated the functions of two fatty acid biosynthesis genes; pod-2, encoding acetyl-CoA carboxylase, and fasn-1, encoding fatty acid synthase, in the C. elegans molting process. Although both the pod-2 and fasn-1 genes were expressed at constant levels throughout C. elegans development, knockdown of the proteins encoded by these genes using RNA interference produced severe defects in triglyceride production, molting, and reproduction that were coupled to suppression of NAS-37, a metalloprotease. An assessment of the structure and integrity of the cuticle using a COL-19::GFP marker and Hoechst 33258 staining showed that downregulation of either pod-2 or fasn-1 impaired cuticle formation and disrupted the integrity of the cuticle and the hypodermal membrane. [BMB reports 2011; 44(4): 285-290]

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