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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 the migration of prostate cancer cells. (A) The cells were placed in the upper chamber inserts with the indicated concentrations of MHY219 and SAHA and allowed to migrate for 24 h. Membranes containing migrated cells were stained, and ten random fields from each experiment were counted under the microscope (×200). (B) Each bar represents the mean ± S.D. of three independent experiments. *p<0.05 as determined by a Student t-test compared to the untreated control.
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f4-bt-23-434: Effect of MHY219 and SAHA on the migration of prostate cancer cells. (A) The cells were placed in the upper chamber inserts with the indicated concentrations of MHY219 and SAHA and allowed to migrate for 24 h. Membranes containing migrated cells were stained, and ten random fields from each experiment were counted under the microscope (×200). (B) Each bar represents the mean ± S.D. of three independent experiments. *p<0.05 as determined by a Student t-test compared to the untreated control.

Mentions: MHY219 inhibitory effect on the migration of prostate cancer cells (DU145, PC3, or LNCaP) was measured using a matrigel migration assay kit. Treatment with MHY219 (1.0 μM) and SAHA (1.0 μM) significantly reduced both LNCaP and PC3 cell migration, but not that of DU145 cells. The migration rate was significantly decreased up to 50% as compared with control in LNCaP cells, below the rate observed for SAHA (Fig. 4). Furthermore, MHY219 effect on metastasis promoting proteins such as MMP1, 2, and 9 was examined using western blot analysis. MHY219 and SAHA treatment significantly decreased MMP-1 and MMP-2 protein expression, but did not affect MMP-9 protein expression (Fig. 5A). MHY219 and SAHA significantly increased TIMP-1 expression levels in both LNCaP and PC3 cells. These data show that MHY219 decreases cellular migration through regulating MMP-1 and MMP-2 protein expression. To confirm the expression levels of migration-related protein expression after MHY219 treatment, we measured MMPs and TIMP-1 mRNA levels in prostate cancer cells. As shown in Fig. 5B, MMP-1 and MMP-2 mRNA levels were significantly decreased after MHY219 treatment (0.5 and 1.0 μM). In addition, TIMP-1 mRNA levels were markedly increased in a concentration-dependent manner after MHY219 treatment.


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 the migration of prostate cancer cells. (A) The cells were placed in the upper chamber inserts with the indicated concentrations of MHY219 and SAHA and allowed to migrate for 24 h. Membranes containing migrated cells were stained, and ten random fields from each experiment were counted under the microscope (×200). (B) Each bar represents the mean ± S.D. of three independent experiments. *p<0.05 as determined by a Student t-test compared to the untreated control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4-bt-23-434: Effect of MHY219 and SAHA on the migration of prostate cancer cells. (A) The cells were placed in the upper chamber inserts with the indicated concentrations of MHY219 and SAHA and allowed to migrate for 24 h. Membranes containing migrated cells were stained, and ten random fields from each experiment were counted under the microscope (×200). (B) Each bar represents the mean ± S.D. of three independent experiments. *p<0.05 as determined by a Student t-test compared to the untreated control.
Mentions: MHY219 inhibitory effect on the migration of prostate cancer cells (DU145, PC3, or LNCaP) was measured using a matrigel migration assay kit. Treatment with MHY219 (1.0 μM) and SAHA (1.0 μM) significantly reduced both LNCaP and PC3 cell migration, but not that of DU145 cells. The migration rate was significantly decreased up to 50% as compared with control in LNCaP cells, below the rate observed for SAHA (Fig. 4). Furthermore, MHY219 effect on metastasis promoting proteins such as MMP1, 2, and 9 was examined using western blot analysis. MHY219 and SAHA treatment significantly decreased MMP-1 and MMP-2 protein expression, but did not affect MMP-9 protein expression (Fig. 5A). MHY219 and SAHA significantly increased TIMP-1 expression levels in both LNCaP and PC3 cells. These data show that MHY219 decreases cellular migration through regulating MMP-1 and MMP-2 protein expression. To confirm the expression levels of migration-related protein expression after MHY219 treatment, we measured MMPs and TIMP-1 mRNA levels in prostate cancer cells. As shown in Fig. 5B, MMP-1 and MMP-2 mRNA levels were significantly decreased after MHY219 treatment (0.5 and 1.0 μM). In addition, TIMP-1 mRNA levels were markedly increased in a concentration-dependent manner after MHY219 treatment.

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