The Class IIa histone deacetylase HDAC4 and neuronal function: Nuclear nuisance and cytoplasmic stalwart?

Fitzsimons, Helen L.

doi:10.1016/j.nlm.2015.06.006

Cited by 37 publications

(28 citation statements)

References 96 publications

(154 reference statements)

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“…The MKK7 transcription identified here is regulated by HDAC4 activity. As a Class IIa HDAC member, HDAC4 is highly expressed in brain cells, and the functions of this protein closely depend on its subcellular localization between the cytoplasm and nucleus . HDAC4 nuclear import‐evoked harmful effects have become known as pathological causes for several disease models, such as ataxia telangiectasia, stroke and Parkinson's disease .…”

Section: Discussionmentioning

confidence: 99%

“…As a Class IIa HDAC member, HDAC4 is highly expressed in brain cells, and the functions of this protein closely depend on its subcellular localization between the cytoplasm and nucleus. 36 HDAC4 nuclear import-evoked harmful effects have become known as pathological causes for several disease models, such as ataxia telangiectasia, 37 stroke 38 and Parkinson's disease. 39 In glioma cells, HDAC4 activity has been implicated in invasion, proliferation, and drug and radiation resistance.…”

Section: Discussionmentioning

confidence: 99%

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MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

Wang

Xia

et al. 2019

Intl Journal of Cancer

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JNK activity has been implicated in the malignant proliferation, invasion and drug‐resistance of glioma cells (GCs), but the molecular mechanisms underlying JNK activation are currently unknown. Here, we reported that MKK7, not MKK4, directly activates JNK in GCs and exerts oncogenic effects on tumor formation. Notably, MKK7 expression in glioma tissues was closely correlated with the grade of the glioma and JNK/c‐Jun activation. Mechanistically, MKK7 transcription critically depends on the complexes formed by HDAC4 and the transcriptional factors SP1 and Krüppel‐like factor‐5 (KLF5), wherein HDAC4 directly deacetylates both SP1 and KLF5 and synergistically upregulates MKK7 transcription through two SP1 sites located on its promoter. In contrast, the increases in acetylated‐SP1 and acetylated‐KLF5 after HDAC4 inhibition switched to transcriptionally suppress MKK7. Selective inhibition of HDAC4 by LMK235, siRNAs or blockage of SP1 and KLF5 by the ectopic dominant‐negative SP1 greatly reduced the malignant capacity of GCs. Furthermore, suppression of both MKK7 expression and JNK/c‐Jun activities was involved in the tumor‐growth inhibitory effects induced by LMK235 in U87‐xenograft mice. Interestingly, HDAC4 is highly expressed in glioma tissues, and the rate of HDAC4 nuclear import is closely correlated with glioma grade, as well as with MKK7 expression. Collectively, these findings demonstrated that highly expressed MKK7 contributes to JNK/c‐Jun signaling‐mediated glioma formation. MKK7 transcription, regulated by SP1 and KLF5, critically depends on HDAC4 activity, and inhibition of HDAC4 presents a potential strategy for suppressing the oncogenic roles of MKK7/JNK/c‐Jun signaling in GCs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

Wang

Xia

et al. 2019

Intl Journal of Cancer

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“…Thus it could be worthwhile to use the INTACT technique (Deal and Henikoff 2011;Henry et al 2012) to investigate HDAC4-dependent gene expression changes in specific neurons in the adult brain (e.g., Kenyon cells). However, given the largely nonnuclear subcellular localization of both mammalian (Darcy et al 2010) and Drosophila HDAC4 (Fitzsimons et al 2013), and the impairment in memory that results from reduction of HDAC4, we have proposed that the presence of HDAC4 is also required for normal memory formation through nontranscriptional mechanisms (Fitzsimons 2015). This led us to extend our search beyond differential gene expression and perform a rough eye screen to identify genes that enhance the HDAC4-induced rough eye phenotype.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Memory inDrosophilaIs Influenced by Histone Deacetylase HDAC4 Interacting with SUMO-Conjugating Enzyme Ubc9

et al. 2016

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HDAC4 is a potent memory repressor with overexpression of wild type or a nuclear-restricted mutant resulting in memory deficits. Interestingly, reduction of HDAC4 also impairs memory via an as yet unknown mechanism. Although histone deacetylase family members are important mediators of epigenetic mechanisms in neurons, HDAC4 is predominantly cytoplasmic in the brain and there is increasing evidence for interactions with nonhistone proteins, suggesting HDAC4 has roles beyond transcriptional regulation.To that end, we performed a genetic interaction screen in Drosophila and identified 26 genes that interacted with HDAC4, including Ubc9, the sole SUMO E2-conjugating enzyme. RNA interference-induced reduction of Ubc9 in the adult brain impaired long-term memory in the courtship suppression assay, a Drosophila model of associative memory. We also demonstrate that HDAC4 and Ubc9 interact genetically during memory formation, opening new avenues for investigating the mechanisms through which HDAC4 regulates memory formation and other neurological processes.KEYWORDS histone deacetylase; SUMOylation; plasticity; neuron; memory T HE histone deacetylase HDAC4 is widely expressed in neurons throughout the brain (Darcy et al. 2010) and an increasing body of evidence indicates that HDAC4 plays important roles in neurological function Chen and Cepko 2009;Kim et al. 2012;Li et al. 2012;Sando et al. 2012;Sarkar et al. 2014). To that end, we recently demonstrated that in Drosophila, RNA interference (RNAi)-mediated knockdown of HDAC4 in the adult brain impairs long-term memory (LTM) in the courtship suppression assay, a model of associative memory (Fitzsimons et al. 2013). Similarly in humans, loss of one copy of HDAC4 correlates with brachydactyly mental retardation syndrome (BDMR), the neurological symptoms of which include intellectual disability and autism (Williams et al. 2010;Morris et al. 2012;Villavicencio-Lorini et al. 2013), and in mice, conditional knockout of HDAC4 in the brain results in impairments in hippocampal-dependent associative LTM . Despite this growing evidence of a critical role, the mechanism(s) through which HDAC4 positively influences LTM is unknown. This is in part because HDAC4 exists in both nuclear and cytoplasmic pools, and under basal conditions, the majority of HDAC4 is localized to the cytoplasm (Chawla et al. 2003;Darcy et al. 2010). Given the predominant nonnuclear localization, particularly the concentration of HDAC4 at dendritic spines (Darcy et al. 2010), we hypothesize that cytoplasmic HDAC4 is required in memory formation; however, the mechanisms through which HDAC4 acts outside the nucleus are unknown.The nuclear role of HDAC4 is less of an enigma. When in the nucleus, HDAC4 acts as a transcriptional repressor; although vertebrate HDAC4 is catalytically inactive as a histone deacetylase, rather it facilitates changes in gene expression through direct binding and inhibition of transcription factors such as MEF2 (Miska et al. 1999;Wang et al. 1999;Lu et al. 2000). As described abov...

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“…Nevertheless, the mechanisms by which chondrocytes sense and respond to mechanical stimulation remain largely unknown. HDAC4 has a surprising ability to translocate between the cytoplasm and nucleus of the cells, and this is thought to play a critical role in cell differentiation and death[19, 23, 24, 36]. Our previous studies[21] showed that HDAC4 regulates growth plate chondrocyte differentiation through relocation from the nucleus in proliferating chondrocytes to the cytoplasm in maturation/prehypertrophic chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

Compression regulates gene expression of chondrocytes through HDAC4 nuclear relocation via PP2A-dependent HDAC4 dephosphorylation

Chen

Wei

Wang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Biomechanics play a critical role in the modulation of chondrocyte function. The mechanisms by which mechanical loading is transduced into intracellular signals that regulate chondrocyte gene expression remain largely unknown. Histone deacetylase 4 (HDAC4) is specifically expressed in chondrocytes. Mice lacking HDAC4 display chondrocyte hypertrophy, ectopic and premature ossification, and die early during the perinatal period. HDAC4 has a remarkable ability to translocate between the cell's cytoplasm and nucleus. It has been established that subcellular relocation of HDAC4 plays a critical role in chondrocyte differentiation and proliferation. However, it remains unclear whether subcellular relocation of HDAC4 in chondrocytes can be induced by mechanical loading. In this study, we first report that compressive loading induces HDAC4 relocation from the cytoplasm to the nucleus of chondrocytes via stimulation of Ser/Thr-phosphoprotein phosphatases 2A (PP2A) activity, which results in dephosphorylation of HDAC4. Dephosphorylated HDAC4 relocates to the nucleus to achieve transcriptional repression of Runx2 and regulates chondrocyte gene expression in response to compression. Our results elucidate the mechanism by which mechanical compression regulates chondrocyte gene expression through HDAC4 relocation from the cell's cytoplasm to the nucleus via PP2A-depended HDAC4 dephosphorylation.

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The Class IIa histone deacetylase HDAC4 and neuronal function: Nuclear nuisance and cytoplasmic stalwart?

Cited by 37 publications

References 96 publications

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

Long-Term Memory inDrosophilaIs Influenced by Histone Deacetylase HDAC4 Interacting with SUMO-Conjugating Enzyme Ubc9

Compression regulates gene expression of chondrocytes through HDAC4 nuclear relocation via PP2A-dependent HDAC4 dephosphorylation

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