Background: HDAC6 plays an important role in cell migration. Results: ERK interacts with and phosphorylates HDAC6 to promote cell migration. Conclusion: ERK signaling pathway promotes cell migration, in part, through phosphorylating HDAC6. Significance: Inhibition of HDAC6 activity as well as the EGFR-Ras-Raf-MEK-ERK signaling pathway may cooperatively reduce cell migration.
Curcumin (diferuloylmethane) is a dietary polyphenol derived from the rhizomes of turmeric (Curcuma longa). For a long time, curcumin has been applied as an anti-inflammatory, 1) anti-oxidative, 2-4) and anti-carcinogenic 5) compound. The multiple therapeutic effects of curcumin result from its ability to modulate enzyme activities and gene expression. For example, curcumin has been shown to down-regulate the activities of several transcription factors, including NF-kappa B, AP-1, and Egr-1, as well as growth factor receptors such as EGFR and HER2. 6) Curcumin also inhibits the activities of COX2, LOX, iNOS, MMP-9, c-Jun N-terminal kinase, protein tyrosine kinases, and protein serine/threonine kinases. 6) Curcumin has been shown to repress expression of oncogenes such as c-fos, c-jun and c-myc, and suppress proliferation of tumour cells. [7][8][9] Finally, recent studies have demonstrated that curcumin can inhibit p300/CBP histone acetyltransferase activity both in vivo and in vitro. 10,11) p300/CBP transfers the acetyl group from an acetyl-CoA to conserved lysine residues in the histones, consequently, leading to transcription activity.12) Therefore, curcumin may modulate gene expression through inhibition of p300/CBP activities.Although the effects of curcumin on enzyme activities and gene expression have been studied in detail, only a few reports described its toxicity to embryos. The studies using rats as animal models have shown that orally administered curcumin has no toxic effects on fertility or pregnancy in the fed rats, and no malformations were observed in their offspring.13) In this report, we used zebrafish (Danio rerio) as model organisms to investigate the developmental toxicity of curcumin. Advantages of using zebrafish as model organisms include their small size (2-4 cm long), ease of breeding in the laboratory, light-induced fertilization, and sensitivity to environmental changes. Our results indicated that, unlike in rats, curcumin had embryotoxic and teratogenic effects on zebrafish embryos in a mM region. MATERIALS AND METHODS Collecting Fertilized Zebrafish EggsAdult zebrafish purchased from a local fish store were maintained in a laboratory under 28Ϯ1°C and a 14 h day/10 h night photoperiod.Fertilized eggs were collected within 30 min after natural mating, washed with sterile water, and placed in petri dishes.Curcumin Treatment and Embryos Observances Curcumin was purchased from Sigma Chemical (St. Louis, MO, U.S.A.), and dissolved in dimethyl sulfoxide (DMSO) to make a 25 mM stock solution. For embryo exposures, fertilized eggs were placed in 6-well petri dishes with ten embryos per well in 10 ml sterile water. Next, 30 ml of seriously diluted curcumin stock solutions was added to get final concentrations of 5, 7.5, 10, 12.5, and 15 mM. Thirty embryos were used for each of four replicates. The embryotoxic and teratogenic effects of resveratrol, quercetin, and rutin were also investigated in this study. Resveratrol, quercetin, and rutin were all purchased from Sigma Chemical (St. Louis, MO...
We have previously discovered that HDAC6 regulates the DNA damage response (DDR) via modulating the homeostasis of a DNA mismatch repair protein, MSH2, through HDAC6’s ubiquitin E3 ligase activity. Here, we have reported HDAC6’s second potential E3 ligase substrate, a critical cell cycle checkpoint protein, Chk1. We have found that HDAC6 and Chk1 directly interact, and that HDAC6 ubiquitinates Chk1 in vivo and in vitro. Specifically, HDAC6 interacts with Chk1 via the DAC1 domain, which contains its ubiquitin E3 ligase activity. During the cell cycle, Chk1 protein levels fluctuate, peaking at the G2 phase, subsequently resolving via the ubiquitin-proteasome pathway, and thereby allowing cells to progress to the M phase. However, in HDAC6 knockdown non-small cell lung cancer (NSCLC) cells, Chk1 is constitutively active and fails to resolve post-ionizing radiation (IR), and this enhanced Chk1 activity leads to preferential G2 arrest in HDAC6 knockdown cells accompanied by a reduction in colony formation capacity and viability. Depletion or pharmacological inhibition of Chk1 in HDAC6 knockdown cells reverses this radiosensitive phenotype, suggesting that the radiosensitivity of HDAC6 knockdown cells is dependent on increased Chk1 kinase activity. Overall, our results highlight a novel mechanism of Chk1 regulation at the post-translational level, and a possible strategy for sensitizing NSCLC to radiation via inhibiting HDAC6’s E3 ligase activity.
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