作者: Okinaga, Toshinori ; Nishihara, Tatsuji ; Fujii, Seiko ; Iwanaga, Kenjiro ; Ariyoshi, Wataru ; Kaneko, Junya ; Hikiji, Hisako ; Tominaga, Kazuhiro

AbstractHistone deacetylase has attracted much attention as an epigenetic factor, and the modulation of histone and transcription factor acetylation status is important for regulating gene expression. Moreover, histone deacetylase inhibitors are involved in cellular growth and differentiation. In the present study, we examined the effects of Ky‐2, a hybrid‐compound HDAC inhibitor, on inflammatory reactions and the polarization of macrophages in vitro. Human monocyte‐like THP‐1 cells were polarized to macrophage‐like cells using phorbol 12‐myristate 13‐acetate, and then polarized to M1 macrophages with LPS. Ky‐2 inhibited HDAC2 expression and enhanced the acetylation of histone H3 in THP‐1 cells. It also downregulated the expression of the IL‐1β‐encoding gene and the LPS‐induced phosphorylation of p38 mitogen‐activated protein kinases in THP‐1 cells. Moreover, the expression of nod‐like receptor protein 3 and cleaved caspase‐1 p20 was downregulated in Ky‐2‐treated THP‐1 cells. In contrast, this agent upregulated the expression of IL‐1ra in LPS‐treated THP‐1 cells. These results indicate that Ky‐2‐treatment downregulates the expression of the inflammatory cytokine, IL‐1β, in LPS‐treated THP‐1 cells, suggesting that Ky‐2 might regulate M1 macrophage polarization through the suppression of inflammatory responses such as NLRP3 inflammasome activation.

2016-04-01·Plant and Cell Physiology2区 · 生物学

Ky-2, a Histone Deacetylase Inhibitor, Enhances High-Salinity Stress Tolerance inArabidopsis thaliana

2区 · 生物学

Article

作者: Saito, Kazuki ; Yoshida, Minoru ; Tanaka, Maho ; Seki, Motoaki ; Nakamura, Kotaro ; Kusano, Miyako ; Matsui, Akihiro ; Kim, Jong-Myong ; Taji, Teruaki ; Nishino, Norikazu ; Kobayashi, Makoto ; Sako, Kaori

Adaptation to environmental stress requires genome-wide changes in gene expression. Histone modifications are involved in gene regulation, but the role of histone modifications under environmental stress is not well understood. To reveal the relationship between histone modification and environmental stress, we assessed the effects of inhibitors of histone modification enzymes during salinity stress. Treatment with Ky-2, a histone deacetylase inhibitor, enhanced high-salinity stress tolerance in Arabidopsis. We confirmed that Ky-2 possessed inhibition activity towards histone deacetylases by immunoblot analysis. To investigate how Ky-2 improved salt stress tolerance, we performed transcriptome and metabolome analysis. These data showed that the expression of salt-responsive genes and salt stress-related metabolites were increased by Ky-2 treatment under salinity stress. A mutant deficient in AtSOS1(Arabidopis thaliana SALT OVERLY SENSITIVE 1), which encodes an Na(+)/H(+)antiporter and was among the up-regulated genes, lost the salinity stress tolerance conferred by Ky-2. We confirmed that acetylation of histone H4 at AtSOS1 was increased by Ky-2 treatment. Moreover, Ky-2 treatment decreased the intracellular Na(+)accumulation under salinity stress, suggesting that enhancement of SOS1-dependent Na(+)efflux contributes to increased high-salinity stress tolerance caused by Ky-2 treatment.

2014-07-01·European Journal of Cancer Prevention4区 · 医学

Chemopreventive and chemotherapeutic effect of a novel histone deacetylase inhibitor, by specificity protein 1 in MDA-MB-231 human breast cancer cells

4区 · 医学

Article

作者: Han, Gyoonhee ; Shin, Ji-Ae ; Kim, Hwan-Mook ; Kim, Hyun-Jung ; Cho, Sung-Dae

Histone deacetylase inhibitors (HDACi) have been reported to have potent chemopreventive activity because of their effects on the inhibition of cell growth and apoptosis in human cancer cell lines. In the present study, we investigated the apoptotic effect of a novel HDACi, Ky2, and its molecular mechanism in MDA-MB-231 human breast cancer cells in vitro. The chemopreventive effects of Ky2 in MDA-MB-231 cells were evaluated using the MTS assay, anchorage-independent cell transformation assay, DAPI staining, western blot analysis, reverse transcriptase-PCR, and small interfering RNA. Ky2 enhanced histone acetylation and decreased cell viability. Ky2 induced apoptosis evidenced by nuclear condensation and fragmentation, the accumulation of sub-G1 phase, and caspase-dependent PARP cleavage. In addition, Ky2 released cytochrome c from mitochondria to cytosol through the regulation of mitochondria-related proteins (Bid, Bim, and Bcl-xL). Ky2 markedly decreased the level of Sp1 protein expression through both the decrease of Sp1 mRNA level and proteasome-dependent protein degradation. Interestingly, the apoptotic effect of Ky2 is more potent than SAHA, a well-known HDACi. Furthermore, the knockdown of Sp1 protein by Sp1-specific inhibitor, mithramycin A, and siRNA resulted in the alteration of truncated Bid and Bim to induce apoptosis. Furthermore, Ky2 significantly decreased TPA-induced or EGF-induced neoplastic cell transformation in JB6 cells. Our results suggest that Ky2 may be a potential chemopreventive and chemotherapeutic agent by modulating Sp1 in human breast cancer cells.

100 项与 KY-2 相关的药物交易

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