HDAC6 regulates sensitivity to cell death in response to stress and post-stress recovery

Ryu, Hyun Wook; Won, Hye Rim; Lee, Dong Hoon; Kwon, So Hee

doi:10.1007/s12192-017-0763-3

Cited by 23 publications

(14 citation statements)

References 46 publications

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“…It may be assumed that pathological modifications impair the functional activity of TDP-43. Two studies showed that oxidative stress caused dramatic CFTR exon 9 inclusion and RNA and protein amounts of the splice-impaired SKAR ␤ isoform were increased upon expression of an aggregation-prone TDP-43 variant (52,53), supporting our findings. Also, HDAC6 mRNA levels were reduced upon overnight exposure with arsenite (52), as is expected when aggregating TDP-43 cannot stabilize the mRNA anymore.…”

Section: Stress Granules and Hyperubiquitylated Insoluble Tdp-43supporting

confidence: 89%

Multiple distinct pathways lead to hyperubiquitylated insoluble TDP-43 protein independent of its translocation into stress granules

Hans¹,

Glasebach²,

Kahle³

2019

J. Biol. Chem.

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Insoluble, hyperubiquitylated TAR DNA-binding protein of 43 kDa (TDP-43) in the central nervous system characterizes frontotemporal dementia and ALS in many individuals with these neurodegenerative diseases. The causes for neuropathological TDP-43 aggregation are unknown, but it has been suggested that stress granule (SG) formation is important in this process. Indeed, in human embryonic kidney HEK293E cells, various SG-forming conditions induced very strong TDP-43 ubiquitylation, insolubility, and reduced splicing activity. Osmotic stress–induced SG formation and TDP-43 ubiquitylation occurred rapidly and coincided with colocalization of TDP-43 and SG markers. Washout experiments confirmed the rapid dissolution of SGs, accompanied by normalization of TDP-43 ubiquitylation and solubility. Surprisingly, interference with the SG process using a protein kinase R–like endoplasmic reticulum kinase inhibitor (GSK2606414) or the translation blocker emetine did not prevent TDP-43 ubiquitylation and insolubility. Thus, parallel pathways may lead to pathological TDP-43 modifications independent of SG formation. Using a panel of kinase inhibitors targeting signaling pathways of the osmotic shock inducer sorbitol, we could largely rule out the stress-activated and extracellular signal–regulated protein kinase modules and glycogen synthase kinase 3β. For arsenite, but not for sorbitol, quenching oxidative stress with N-acetylcysteine did suppress both SG formation and TDP-43 ubiquitylation and insolubility. Thus, sodium arsenite appears to promote SG formation and TDP-43 modifications via oxidative stress, but sorbitol stimulates TDP-43 ubiquitylation and insolubility via a novel pathway(s) independent of SG formation. In conclusion, pathological TDP-43 modifications can be mediated via multiple distinct pathways for which SGs are not essential.

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Section: Stress Granules and Hyperubiquitylated Insoluble Tdp-43supporting

confidence: 89%

Multiple distinct pathways lead to hyperubiquitylated insoluble TDP-43 protein independent of its translocation into stress granules

Hans¹,

Glasebach²,

Kahle³

2019

J. Biol. Chem.

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“…A452 is a small-molecule inhibitor with a γ-lactam that selectively inhibits HDAC6 catalytic activity in various human cancer cells [ 33 ]. Recently, A452 demonstrated significant anticancer activity in solid tumors and blood cancers, including MM [ 35 , 36 , 37 , 38 ]. We, therefore, sought to determine whether A452 has antimyeloma activity in both BTZ-sensitive U266 and BTZ-resistant U266/VelR cells.…”

Section: Resultsmentioning

confidence: 99%

HDAC6-Selective Inhibitor Overcomes Bortezomib Resistance in Multiple Myeloma

Lee

Yeon

Kim

et al. 2021

IJMS

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Although multiple myeloma (MM) patients benefit from standard bortezomib (BTZ) chemotherapy, they develop drug resistance, resulting in relapse. We investigated whether histone deacetylase 6 (HDAC6) inhibitor A452 overcomes bortezomib resistance in MM. We show that HDAC6-selective inhibitor A452 significantly decreases the activation of BTZ-resistant markers, such as extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-κB), in acquired BTZ-resistant MM cells. Combination treatment of A452 and BTZ or carfilzomib (CFZ) synergistically reduces BTZ-resistant markers. Additionally, A452 synergizes with BTZ or CFZ to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3), resulting in decreased expressions of low-molecular-mass polypeptide 2 (LMP2) and LMP7. Furthermore, combining A452 with BTZ or CFZ leads to synergistic cancer cell growth inhibition, viability decreases, and apoptosis induction in the BTZ-resistant MM cells. Overall, the synergistic effect of A452 with CFZ is more potent than that of A452 with BTZ in BTZ-resistant U266 cells. Thus, our findings reveal the HDAC6-selective inhibitor as a promising therapy for BTZ-chemoresistant MM.

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“…HDAC6 contains two catalytic domains for deacetylation, which are separated by the dynein‐binding domain [57,62,63], a SE14 domain, and a C terminus cysteine‐ and histidine‐rich ZnF‐UBP (zinc‐finger ubiquitin‐binding protein) domain [59]. In particular, the ZnF‐UBP domain plays a critical role in the function of HDAC6 in the cellular stress response pathway [64,65]. HDAC6 binds G3BP‐1 to regulate stress granule formation [66].…”

Section: Mk‐styx Promotes Dephosphorylation Of Histone Deacetylasementioning

confidence: 99%

Pseudophosphatase MK‐STYX: the atypical member of the MAP kinase phosphatases

Hinton

2020

The FEBS Journal

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The regulation of the phosphorylation of mitogen-activated protein kinases (MAPKs) is essential for cellular processes such as proliferation, differentiation, survival, and death. Mutations within the MAPK signaling cascades are implicated in diseases such as cancer, neurodegenerative disorders, arthritis, obesity, and diabetes. MAPK phosphorylation is controlled by an intricate balance between MAPK kinases (enzymes that add phosphate groups) and MAPK phosphatases (MKPs) (enzymes that remove phosphate groups). MKPs are complex negative regulators of the MAPK pathway that control the amplitude and spatiotemporal regulation of MAPKs. MK-STYX (MAPK phosphoserine/threonine/tyrosine-binding protein) is a member of the MKP subfamily, which lacks the critical histidine and nucleophilic cysteine residues in the active site required for catalysis. MK-STYX does not influence the phosphorylation status of MAPK, but even so it adds to the complexity of signal transduction cascades as a signaling regulator. This review highlights the function of MK-STYX, providing insight into MK-STYX as a signal regulating molecule in the stress response, HDAC 6 dynamics, apoptosis, and neurite differentiation. Abbreviations CH2, cell division cycle 25 phosphatase homology 2; DUSP, dual-specificity phosphatase; FBXW7, F-box and WD repeat domain containing 7; HDAC6, histone deacetylase 6; MAPK, mitogen-activated protein kinase; MKP, MAPK phosphatase; MK-STYX, MAPK phosphoserine/ threonine/tyrosine-binding protein; MTM, myotubularin; PTP, protein tyrosine phosphatase; STYX, phosphoserine/threonine/tyrosineinteracting protein.

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HDAC6 regulates sensitivity to cell death in response to stress and post-stress recovery

Cited by 23 publications

References 46 publications

Multiple distinct pathways lead to hyperubiquitylated insoluble TDP-43 protein independent of its translocation into stress granules

Multiple distinct pathways lead to hyperubiquitylated insoluble TDP-43 protein independent of its translocation into stress granules

HDAC6-Selective Inhibitor Overcomes Bortezomib Resistance in Multiple Myeloma

Pseudophosphatase MK‐STYX: the atypical member of the MAP kinase phosphatases

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