Class I HDAC inhibition is a novel pathway for regulating astrocytic apoE secretion

Dresselhaus, Erica C.; Duerr, James M.; Vincent, Fabien; Sylvain, Emily; Beyna, Mercedes; Lanyon, Lorraine F.; LaChapelle, Erik; Pettersson, Martin; Bales, Kelly R.; Ramaswamy, Gayathri

doi:10.1371/journal.pone.0194661

Cited by 22 publications

(16 citation statements)

References 58 publications

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“…6,27,42,43 Interestingly, a previous study found that in particular inhibiting the class I HDACs, however, independent of regulating the LXR pathway, upregulated the secretion of ApoE in a human astrocytoma cell line. 44 In the CNS, ApoE is an important protein required for the binding and the export of lipids. A schematic summary of MS-275-regulated lipid pathways in human HAP1 cells and primary macrophages is shown in Figure 8.…”

Section: Discussionmentioning

confidence: 99%

Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS‐275

Zierfuss

Weinhofer

Buda

et al. 2020

Ann Clin Transl Neurol

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Objective: To assess class I-histone deacetylase (HDAC) inhibition on formation of lipid-accumulating, disease-promoting phagocytes upon myelin load in vitro, relevant for neuroinflammatory disorders like multiple sclerosis (MS) and cerebral X-linked adrenoleukodystrophy (X-ALD). Methods: Immunohistochemistry on postmortem brain tissue of acute MS (n = 6) and cerebral ALD (n = 4) cases to analyze activation and foam cell state of phagocytes. RNA-Seq of in vitro differentiated healthy macrophages (n = 8) after sustained myelinloading to assess the metabolic shift associated with foam cell formation. RNA-Seq analysis of genes linked to lipid degradation and export in MS-275-treated human HAP1 cells and RT-qPCR analysis of HAP1 cells knocked out for individual members of class I HDACs or the corresponding enzymatically inactive knock-in mutants. Investigation of intracellular lipid/myelin content after MS-275 treatment of myelin-laden human foam cells. Analysis of disease characteristic very long-chain fatty acid (VLCFA) metabolism and inflammatory state in MS-275-treated X-ALD macrophages. Results: Enlarged foam cells coincided with a pro-inflammatory, lesion-promoting phenotype in postmortem tissue of MS and cerebral ALD patients. Healthy in vitro myelin laden foam cells upregulated genes linked to LXRa/PPARc pathways and mimicked a program associated with tissue repair. Treating these cells with MS-275, amplified this gene transcription program and significantly reduced lipid and cholesterol accumulation and, thus, foam cell formation. In macrophages derived from X-ALD patients, MS-275 improved the disease-associated alterations of VLCFA metabolism and reduced the pro-inflammatory status of these cells. Interpretation: These findings identify class I-HDAC inhibition as a potential novel strategy to prevent disease promoting foam cell formation in CNS inflammation.

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Section: Discussionmentioning

confidence: 99%

Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS‐275

Zierfuss

Weinhofer

Buda

et al. 2020

Ann Clin Transl Neurol

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“…Histone deacetylases (HDACs) are a class of molecules known to be associated with extracellular signals in tumor cells. The different isoforms of HDAC have been demonstrated to alter the protein content in exosomes 24 and the repertoire of the soluble proteins secreted by tumor cells 25,26 . In GBM, the intracellular function of HDACs is known to regulate the DNA damage response 27 and brain parenchyma invasion 28 by modulating the NF-κB and other pathways 29 , Nonetheless, the effects of HDACs on intratumoral spatial crosstalk remain unknown.…”

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confidence: 99%

Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy

et al. 2020

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Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM heterogeneity is largely limited to the surgically resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrates clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Upon xenotransplantation, edge-derived cells show a higher capacity for infiltrative growth, while core cells demonstrate core lesions with greater therapy resistance. Investigation of intercellular signaling between these two tumor populations uncovers the paracrine crosstalk from tumor core that promotes malignancy and therapy resistance of edge cells. These phenotypic alterations are initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence.

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“…A recent study identified Ondansetron, an FDA-approved 5-HT3 antagonist, as an apoE modulator that also involves the LXR pathway [48]. As LXR activation is undesirable due to hepatotoxic side effects, several studies have aimed to identify LXR-independent pathways that stimulate apoE expression and these have returned inhibitors of 3β-hydroxysterol Δ(24)-reductase, 7dehydrocholesterol reductase, and pan class I histone deacetylases [49,50], lending support that apoE production and lipidation can be regulated though LXR-independent pathways in the CNS. AZ7235 is from a distinct class of apoE modulators that targets Axl, an RTK that belongs to the TAM (TYRO3, Axl, and MERTK) family.…”

Section: Discussionmentioning

confidence: 99%

Axl receptor tyrosine kinase is a regulator of apolipoprotein E

et al. 2020

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Alzheimer's disease (AD), the leading cause of dementia, is a chronic neurodegenerative disease. Apolipoprotein E (apoE), which carries lipids in the brain in the form of lipoproteins, plays an undisputed role in AD pathophysiology. A high-throughput phenotypic screen was conducted using a CCF-STTG1 human astrocytoma cell line to identify small molecules that could upregulate apoE secretion. AZ7235, a previously discovered Axl kinase inhibitor, was identified to have robust apoE activity in brain microglia, astrocytes and pericytes. AZ7235 also increased expression of ATP-binding cassette protein A1 (ABCA1), which is involved in the lipidation and secretion of apoE. Moreover, AZ7235 did not exhibit Liver-X-Receptor (LXR) activity and stimulated apoE and ABCA1 expression in the absence of LXR. Target validation studies using AXL−/− CCF-STTG1 cells showed that Axl is required to mediate AZ7235 upregulation of apoE and ABCA1. Intriguingly, apoE expression and secretion was significantly attenuated in AXLdeficient CCF-STTG1 cells and reconstitution of Axl or kinase-dead Axl significantly restored apoE baseline levels, demonstrating that Axl also plays a role in maintaining apoE homeostasis in astrocytes independent of its kinase activity. Lastly, these effects may require human apoE regulatory sequences, as AZ7235 exhibited little stimulatory activity toward apoE and ABCA1 in primary murine glia derived from neonatal human APOE3 targeted-replacement mice. Collectively, we identified a small molecule that exhibits robust apoE and ABCA1 activity independent of the LXR pathway in human cells and elucidated a novel relationship between Axl and apoE homeostasis in human astrocytes.

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Class I HDAC inhibition is a novel pathway for regulating astrocytic apoE secretion

Cited by 22 publications

References 58 publications

Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS‐275

Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS‐275

Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy

Axl receptor tyrosine kinase is a regulator of apolipoprotein E

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