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Loss of deacetylation activity of Hdac6 affects emotional behavior in mice.

ABSTRACT: Acetylation is mediated by acetyltransferases and deacetylases, and occurs not only on histones but also on diverse proteins. Although histone acetylation in chromatin structure and transcription has been well studied, the biological roles of non-histone acetylation remain elusive. Histone deacetylase 6 (Hdac6), a member of the histone deacetylase (HDAC) family, is a unique deacetylase that localizes to cytoplasm and functions in many cellular events by deacetylating non-histone proteins including ?-tubulin, Hsp90, and cortactin. Since robust expression of Hdac6 is observed in brain, it would be expected that Hdac6-mediated reversible acetylation plays essential roles in CNS. Here we demonstrate the crucial roles of Hdac6 deacetylase activity in the expression of emotional behavior in mice. We found that Hdac6-deficient mice exhibit hyperactivity, less anxiety, and antidepressant-like behavior in behavioral tests. Moreover, administration of Hdac6-specific inhibitor replicated antidepressant-like behavior in mice. In good agreement with behavioral phenotypes of Hdac6-deficient mice, Hdac6 dominantly localizes to the dorsal and median raphe nuclei, which are involved in emotional behaviors. These findings suggest that HDAC6-mediated reversible acetylation might contribute to maintain proper neuronal activity in serotonergic neurons, and also provide a new therapeutic target for depression.

SUBMITTER: Fukada M

PROVIDER: S-EPMC3273475 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Loss of deacetylation activity of Hdac6 affects emotional behavior in mice.

Fukada Masahide M Hanai Atsuko A Nakayama Atsuo A Suzuki Takayoshi T Miyata Naoki N Rodriguiz Ramona M RM Wetsel William C WC Yao Tso-Pang TP Kawaguchi Yoshiharu Y

PloS one 20120206 2

Acetylation is mediated by acetyltransferases and deacetylases, and occurs not only on histones but also on diverse proteins. Although histone acetylation in chromatin structure and transcription has been well studied, the biological roles of non-histone acetylation remain elusive. Histone deacetylase 6 (Hdac6), a member of the histone deacetylase (HDAC) family, is a unique deacetylase that localizes to cytoplasm and functions in many cellular events by deacetylating non-histone proteins includi ...[more]

PMID: 22328923

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Project description:The AKT family of serine-threonine kinases functions downstream of phosphatidylinositol 3-kinase (PI3K) to transmit signals by direct phosphorylation of a number of targets, including the mammalian target of rapamycin (mTOR), glycogen synthase kinase 3? (GSK3?), and ?-catenin. AKT binds to phosphatidylinositol (3,4,5)-triphosphate (PIP3) generated by PI3K activation, which results in its membrane localization and subsequent activation through phosphorylation by phosphoinositide-dependent protein kinase 1 (PDK1). Together, the PI3K-AKT signaling pathway plays pivotal roles in many cellular systems, including in the central nervous system where it governs both neurodevelopment and neuroplasticity. Recently, lysine residues (Lys14 and Lys20) on AKT, located within its pleckstrin homology (PH) domain that binds to membrane-bound PIP3, have been found to be acetylated under certain cellular contexts in various cancer cell lines. These acetylation modifications are removed by the enzymatic action of the class III lysine deacetylases, SIRT1 and SIRT2, of the sirtuin family. The extent to which reversible acetylation regulates AKT function in other cell types remains poorly understood. We report here that AKT kinase activity is modulated by a class IIb lysine deacetylase, histone deacetylase 6 (HDAC6), in human neural progenitor cells (NPCs). We find that HDAC6 and AKT physically interact with each other in the neuronal cells, and in the presence of selective HDAC6 inhibition, AKT is acetylated at Lys163 and Lys377 located in the kinase domain, two novel sites distinct from the acetylation sites in the PH-domain modulated by the sirtuins. Measurement of the functional effect of HDAC6 inhibition on AKT revealed decreased binding to PIP3, a correlated decrease in AKT kinase activity, decreased phosphorylation of Ser552 on ?-catenin, and modulation of neuronal differentiation trajectories. Taken together, our studies implicate the deacetylase activity of HDAC6 as a novel regulator of AKT signaling and point to novel mechanisms for regulating AKT activity with small-molecule inhibitors of HDAC6 currently under clinical development.

Project description:BackgroundHighly proliferating cancer cells exhibit the Warburg effect by regulation of PKM alternative splicing and promoting the expression of PKM2. Majority of the alternative splicing events are known to occur in the nuclear matrix where various MARBPs actively participate in the alternative splicing events. SMAR1, being a MARBP and an important tumor suppressor, is known to regulate the splicing of various cancer-associated genes. This study focuses on the regulation of PKM alternative splicing and inhibition of the Warburg effect by SMAR1.MethodsImmunohistochemistry was performed in breast cancer patient samples to establish the correlation between SMAR1 and PKM isoform expression. Further, expression of PKM isoforms upon modulation in SMAR1 expression in breast cancer cell lines was quantified by qRT-PCR and western blot. The acetylation status of PTBP1 was estimated by immunoprecipitation along with its enrichment on PKM pre-mRNA by CLIP in SMAR1 knockdown conditions. The role of SMAR1 in tumor metabolism and tumorigenesis was explored by in vitro enzymatic assays and functional assays upon SMAR1 knockdown. Besides, in vivo tumor formation by injecting adeno-SMAR1-transduced MDA-MB-231 cells in NOD/SCID mice was performed.ResultsThe expression profile of SMAR1 and PKM isoforms in breast cancer patients revealed that SMAR1 has an inverse correlation with PKM2 and a positive correlation with PKM1. Further quantitative PKM isoform expression upon modulation in SMAR1 expression also reflects that SMAR1 promotes the expression of PKM1 over tumorigenic isoform PKM2. SMAR1 deacetylates PTBP1 via recruitment of HDAC6 resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. SMAR1 inhibits the Warburg effect, tumorigenic potential of cancer cells, and in vivo tumor generation in a PKM2-dependent manner.ConclusionsSMAR1 regulates PKM alternative splicing by causing HDAC6-dependent deacetylation of PTBP1, resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. Additionally, SMAR1 suppresses glucose utilization and lactate production via repression of PKM2 expression. This suggests that tumor suppressor SMAR1 inhibits tumor cell metabolism and tumorigenic properties of cancer cells via regulation of PKM alternative splicing.

Dataset Information

Loss of deacetylation activity of Hdac6 affects emotional behavior in mice.

Publications

Loss of deacetylation activity of Hdac6 affects emotional behavior in mice.

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