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A New Histone Deacetylase Inhibitor, MHY219, Inhibits the Migration of Human Prostate Cancer Cells via HDAC1.

De U, Kundu S, Patra N, Ahn MY, Ahn JH, Son JY, Yoon JH, Moon HR, Lee BM, Kim HS - Biomol Ther (Seoul) (2015)

Bottom Line: MHY219 significantly inhibited the HDAC1 protein levels in LNCaP and DU145 cells at high concentrations.However, inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type.MHY219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease-1 (MMP-1) and MMP-2 and induction of tissue inhibitor of metalloproteinases-1 (TIMP-1).

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746.

ABSTRACT
Histone deacetylase (HDAC) inhibitors are considered novel agents for cancer chemotherapy. We previously investigated MHY219, a new HDAC inhibitor, and its potent anticancer activity in human prostate cancer cells. In the present study, we evaluated MHY219 molecular mechanisms involved in the regulation of prostate cancer cell migration. Similar to suberanilohydroxamic acid (SAHA), MHY219 inhibited HDAC1 enzyme activity in a dose-dependent manner. MHY219 cytotoxicity was higher in LNCaP (IC50=0.67 μM) than in DU145 cells (IC50=1.10 μM) and PC3 cells (IC50=5.60 μM) after 48 h of treatment. MHY219 significantly inhibited the HDAC1 protein levels in LNCaP and DU145 cells at high concentrations. However, inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type. MHY219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease-1 (MMP-1) and MMP-2 and induction of tissue inhibitor of metalloproteinases-1 (TIMP-1). These results suggest that MHY219 may potentially be used as an anticancer agent to block cancer cell migration through the repression of MMP-1 and MMP-2, which is related to the reduction of HDAC1.

No MeSH data available.


Related in: MedlinePlus

Effect of MHY219 and SAHA on histone deacetylase (HDAC) 1 activity and expression levels of HDACs in prostate cancer cells. (A) Histone deacetylase 1 (HDAC1) enzyme activity was measured by using a fluorometric HDAC activity assay kit. This result represents the percentage of activity compared to control cells in each group, respectively. Results are expressed as mean ± standard error of the mean (S.E.M.) of three independent experiments. *p<0.05, **p<0.01 as determined by Student t-test compared to the control. (B) LNCaP, DU145, and PC3 cells were treated with the indicated concentrations of MHY219 and SAHA for 48 h and HDAC (class I and II) expression levels were measured by western blot analysis. Histone 1 was used as a housekeeping control protein. (C) Densitometric analysis of HDAC1, HDAC2, HDAC3, or HDAC4 ratio, respectively. Bars represent mean ± S.E.M of three independent experiments. *p<0.05, **p<0.01 as determined by Student t-test compared to the control.
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f2-bt-23-434: Effect of MHY219 and SAHA on histone deacetylase (HDAC) 1 activity and expression levels of HDACs in prostate cancer cells. (A) Histone deacetylase 1 (HDAC1) enzyme activity was measured by using a fluorometric HDAC activity assay kit. This result represents the percentage of activity compared to control cells in each group, respectively. Results are expressed as mean ± standard error of the mean (S.E.M.) of three independent experiments. *p<0.05, **p<0.01 as determined by Student t-test compared to the control. (B) LNCaP, DU145, and PC3 cells were treated with the indicated concentrations of MHY219 and SAHA for 48 h and HDAC (class I and II) expression levels were measured by western blot analysis. Histone 1 was used as a housekeeping control protein. (C) Densitometric analysis of HDAC1, HDAC2, HDAC3, or HDAC4 ratio, respectively. Bars represent mean ± S.E.M of three independent experiments. *p<0.05, **p<0.01 as determined by Student t-test compared to the control.

Mentions: The effect of MHY219 on HDAC1 enzyme activity was examined using the fluorometric HDAC1 enzyme assay kit. As shown in Fig. 2A, MHY219 significantly inhibited HDAC1 enzyme activity in a concentration-dependent manner with an IC50 value of 0.276 μM, which was similar to that of SAHA (IC50=0.254 μM). In our previous study, the effect of MHY219 on total HDAC enzyme activity was measured. As a result, MHY219 significantly inhibited total HDAC enzyme activity in a concentration-dependent manner (Patra et al., 2013). We next examined MHY219 inhibitory effect on the expression of specific HDACs isoforms in human prostate cancer cells. MHY219 effect on the expression of HDAC1, 2, 3, and 4 was identified by western blot analysis. A significant decrease in HDAC1 and HDAC2 levels was observed in LNCaP cells after MHY219 treatment. HDAC1, 2, 3, and 4 in DU145 cells were downregulated after MHY219 treatment. No change in HDAC1 was observed in PC3 cells (Fig. 2B).


A New Histone Deacetylase Inhibitor, MHY219, Inhibits the Migration of Human Prostate Cancer Cells via HDAC1.

De U, Kundu S, Patra N, Ahn MY, Ahn JH, Son JY, Yoon JH, Moon HR, Lee BM, Kim HS - Biomol Ther (Seoul) (2015)

Effect of MHY219 and SAHA on histone deacetylase (HDAC) 1 activity and expression levels of HDACs in prostate cancer cells. (A) Histone deacetylase 1 (HDAC1) enzyme activity was measured by using a fluorometric HDAC activity assay kit. This result represents the percentage of activity compared to control cells in each group, respectively. Results are expressed as mean ± standard error of the mean (S.E.M.) of three independent experiments. *p<0.05, **p<0.01 as determined by Student t-test compared to the control. (B) LNCaP, DU145, and PC3 cells were treated with the indicated concentrations of MHY219 and SAHA for 48 h and HDAC (class I and II) expression levels were measured by western blot analysis. Histone 1 was used as a housekeeping control protein. (C) Densitometric analysis of HDAC1, HDAC2, HDAC3, or HDAC4 ratio, respectively. Bars represent mean ± S.E.M of three independent experiments. *p<0.05, **p<0.01 as determined by Student t-test compared to the control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556203&req=5

f2-bt-23-434: Effect of MHY219 and SAHA on histone deacetylase (HDAC) 1 activity and expression levels of HDACs in prostate cancer cells. (A) Histone deacetylase 1 (HDAC1) enzyme activity was measured by using a fluorometric HDAC activity assay kit. This result represents the percentage of activity compared to control cells in each group, respectively. Results are expressed as mean ± standard error of the mean (S.E.M.) of three independent experiments. *p<0.05, **p<0.01 as determined by Student t-test compared to the control. (B) LNCaP, DU145, and PC3 cells were treated with the indicated concentrations of MHY219 and SAHA for 48 h and HDAC (class I and II) expression levels were measured by western blot analysis. Histone 1 was used as a housekeeping control protein. (C) Densitometric analysis of HDAC1, HDAC2, HDAC3, or HDAC4 ratio, respectively. Bars represent mean ± S.E.M of three independent experiments. *p<0.05, **p<0.01 as determined by Student t-test compared to the control.
Mentions: The effect of MHY219 on HDAC1 enzyme activity was examined using the fluorometric HDAC1 enzyme assay kit. As shown in Fig. 2A, MHY219 significantly inhibited HDAC1 enzyme activity in a concentration-dependent manner with an IC50 value of 0.276 μM, which was similar to that of SAHA (IC50=0.254 μM). In our previous study, the effect of MHY219 on total HDAC enzyme activity was measured. As a result, MHY219 significantly inhibited total HDAC enzyme activity in a concentration-dependent manner (Patra et al., 2013). We next examined MHY219 inhibitory effect on the expression of specific HDACs isoforms in human prostate cancer cells. MHY219 effect on the expression of HDAC1, 2, 3, and 4 was identified by western blot analysis. A significant decrease in HDAC1 and HDAC2 levels was observed in LNCaP cells after MHY219 treatment. HDAC1, 2, 3, and 4 in DU145 cells were downregulated after MHY219 treatment. No change in HDAC1 was observed in PC3 cells (Fig. 2B).

Bottom Line: MHY219 significantly inhibited the HDAC1 protein levels in LNCaP and DU145 cells at high concentrations.However, inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type.MHY219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease-1 (MMP-1) and MMP-2 and induction of tissue inhibitor of metalloproteinases-1 (TIMP-1).

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746.

ABSTRACT
Histone deacetylase (HDAC) inhibitors are considered novel agents for cancer chemotherapy. We previously investigated MHY219, a new HDAC inhibitor, and its potent anticancer activity in human prostate cancer cells. In the present study, we evaluated MHY219 molecular mechanisms involved in the regulation of prostate cancer cell migration. Similar to suberanilohydroxamic acid (SAHA), MHY219 inhibited HDAC1 enzyme activity in a dose-dependent manner. MHY219 cytotoxicity was higher in LNCaP (IC50=0.67 μM) than in DU145 cells (IC50=1.10 μM) and PC3 cells (IC50=5.60 μM) after 48 h of treatment. MHY219 significantly inhibited the HDAC1 protein levels in LNCaP and DU145 cells at high concentrations. However, inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type. MHY219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease-1 (MMP-1) and MMP-2 and induction of tissue inhibitor of metalloproteinases-1 (TIMP-1). These results suggest that MHY219 may potentially be used as an anticancer agent to block cancer cell migration through the repression of MMP-1 and MMP-2, which is related to the reduction of HDAC1.

No MeSH data available.


Related in: MedlinePlus