Down-Regulation of Deacetylase HDAC6 Inhibits the Melanoma Cell Line A375.S2 Growth through ROS-Dependent Mitochondrial Pathway

Bai, Jun; Lei, Yun; An, Gaili; He, Li

doi:10.1371/journal.pone.0121247

Cited by 38 publications

(44 citation statements)

References 27 publications

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“…This finding is in keeping with a previous study that showed that an HDAC6 inhibitor improved survival and reduced bacteremia in a murine sepsis model (35). Moreover, previous studies have linked HDAC6 to the control of mitochondrial function (43,44), and a very recent study reported that HDAC6 inhibition disrupted mitochondrial membrane potential and enhanced ROS production in melanoma cells (45). Collectively, these studies suggest that HDAC6 may have a regulatory role in controlling mitoROS production in infected macrophages such that inhibition of HDAC6 increases mitoROS concentrations to facilitate bacterial clearance.…”

Section: Discussionsupporting

confidence: 91%

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Ariffin

Gupta

Kapétanovic

et al. 2016

Antimicrob Agents Chemother

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Broad-spectrum histone deacetylase inhibitors (HDACi) are used clinically as anticancer agents, and more isoform-selective HDACi have been sought to modulate other conditions, including chronic inflammatory diseases. Mouse studies suggest that HDACi downregulate immune responses and may compromise host defense. However, their effects on human macrophage antimicrobial responses are largely unknown. Here, we show that overnight pretreatment of human macrophages with HDACi prior to challenge with Salmonella enterica serovar Typhimurium or Escherichia coli results in significantly reduced intramacrophage bacterial loads, which likely reflect the fact that this treatment regime impairs phagocytosis. In contrast, cotreatment of human macrophages with HDACi at the time of bacterial challenge did not impair phagocytosis; instead, HDACi cotreatment actually promoted clearance of intracellular S. Typhimurium and E. coli. Mechanistically, treatment of human macrophages with HDACi at the time of bacterial infection enhanced mitochondrial reactive oxygen species generation by these cells. The capacity of HDACi to promote the clearance of intracellular bacteria from human macrophages was abrogated when cells were pretreated with MitoTracker Red CMXRos, which perturbs mitochondrial function. The HDAC6-selective inhibitor tubastatin A promoted bacterial clearance from human macrophages, whereas the class I HDAC inhibitor MS-275, which inhibits HDAC1 to -3, had no effect on intracellular bacterial loads. These data are consistent with HDAC6 and/or related HDACs constraining mitochondrial reactive oxygen species production from human macrophages during bacterial challenge. Our findings suggest that, whereas long-term HDACi treatment regimes may potentially compromise host defense, selective HDAC inhibitors may have applications in treating acute bacterial infections.

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Section: Discussionsupporting

confidence: 91%

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Ariffin

Gupta

Kapétanovic

et al. 2016

Antimicrob Agents Chemother

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“…HDAC6 has been designated as a potential therapeutic target, and a number of specific HDAC6 inhibitors (HDAC6i) have been developed (7). Preclinical data suggest that small molecule-specific HDAC6i may play a role in treatment of certain cancers, neurodegenerative diseases, and autoimmune disorders (3,4,8,11,51). In addition, HDAC6 inhibitors have also been tested in some acute injury models.…”

Section: Increase Of Acetylationmentioning

confidence: 99%

“…Of the 11 isoforms of HDACs, HDAC6 is unique among histone deacetylases: existing predominantly in the cytoplasm, it is able to deacetylate nonhistone proteins in the cytoplasm (23). Increasing evidence has indicated that the function of HDAC6 is not limited to tumorgenesis but also implicated in some chronic diseases such as neurodegenerative diseases, cardiovascular disease, fibrosis, and cystogenesis (3,4,8,11,51). Interestingly, recent studies have shown that HDAC6 activation is also associated with pathogenesis of acute organ/ tissue injury (9,25,38,46).…”

mentioning

confidence: 99%

Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury

Shi

Tang

et al. 2017

American Journal of Physiology-Renal Physiology

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Histone deacetylase 6 (HDAC6) inhibition has been reported to protect against ischemic stroke and prolong survival after sepsis in animal models. However, it remains unknown whether HDAC6 inhibition offers a renoprotective effect after acute kidney injury (AKI). In this study, we examined the effect of tubastatin A (TA), a highly selective inhibitor of HDAC6, on AKI in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe acute tubular injury as indicated by renal dysfunction; expression of neutrophil gelatinase-associated lipocalin (NGAL), an injury marker of renal tubules; and an increase of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. These changes were companied by increased HDAC6 expression in the cytoplasm of renal tubular cells. Administration of TA significantly reduced serum creatinine and blood urea nitrogen levels as well as attenuated renal tubular damage in injured kidneys. HDAC6 inhibition also resulted in decreased expression of NGAL, reduced apoptotic cell, and inactivated caspase-3 in the kidney after acute injury. Moreover, injury to the kidney increased phosphorylation of nuclear factor (NF)-κB and expression of multiple cytokines/chemokines including tumor necrotic factor-α and interleukin-6 and monocyte chemoattractant protein-1, as well as macrophage infiltration. Treatment with TA attenuated all those responses. Finally, HDAC6 inhibition reduced the level of oxidative stress by suppressing malondialdehyde (MDA) and preserving expression of superoxide dismutase (SOD) in the injured kidney. Collectively, these data indicate that HDAC6 contributes to the pathogenesis of rhabdomyolysis-induced AKI and suggest that HDAC6 inhibitors have therapeutic potential for AKI treatment.

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“…3.4 | Elevated ROS level in mouse embryos exposed to TubA It has been indicated that HDAC6 is involved in the modulation of mitochondrial transport and the balance between mitochondrial biogenesis and degradation (Bai et al, 2015;Chen et al, 2010;C. Kim et al, 2012).…”

Section: Hdac6 Inhibition Disrupts the Chromosomal Congression In Mmentioning

confidence: 99%

HDAC6 inhibition induces the failure of mouse early embryonic development

Wang

et al. 2018

Journal Cellular Physiology

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Histone deacetylases (HDACs) have been implicated in numerous biological events. However, to date, the role of HDAC6 in early embryos remains unknown. In the current study, Tubastatin A (TubA), a potent HDAC6 inhibitor, was used to block HDAC6 activity in mouse embryos. We found that TubA exposure significantly reduced the blastocyst formation of early embryos. Confocal microscopy revealed the markedly increased chromosomal congression failure in the mouse embryos treated with the HDAC6 inhibitor. Moreover, the HDAC6 inhibition resulted in the overproduction of reactive oxygen species (ROS) in embryos. In addition, we observed the accumulation of phosphorylated γH2AX in TubA‐treated embryos, indicative of the increased DNA damage. In line with this, cell apoptosis of blastocysts was frequently detected in HDAC6‐deficient embryos compared with their controls. Altogether, our data indicate that HDAC6 may serve as an important regulator of chromatin structure and mitochondrial function, determining the developmental potential of the early embryos of mouse.

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Down-Regulation of Deacetylase HDAC6 Inhibits the Melanoma Cell Line A375.S2 Growth through ROS-Dependent Mitochondrial Pathway

Cited by 38 publications

References 27 publications

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury

HDAC6 inhibition induces the failure of mouse early embryonic development

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