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Class I HDAC inhibitor mocetinostat induces apoptosis by activation of miR-31 expression and suppression of E2F6

View Article: PubMed Central - PubMed

ABSTRACT

The class I selective inhibitor of the histone deacetylases, mocetinostat, has promising antitumor activities in both preclinical studies and the clinical trials. To understand how mocetinostat induces apoptosis, we examined the effects of mocetinostat on miR-31, a proapoptotic microRNA that was previously found to be epigenetically silenced in prostate cancer. We found that miR-31 was significantly upregulated by mocetinostat in prostate cancer cells. Antiapoptotic protein E2F6, the target of miR-31, was decreased by mocetinostat treatment. When miR-31 was blocked with an inhibitor, the ability of mocetinostat to induce apoptosis was reduced. We further demonstrated that mocetinostat enhanced the activity of docetaxel in apoptosis induction. While siRNA knockdown of E2F6 sensitized cancer cells to mocetinostat-induced apoptosis, overexpression of E2F6 blocked mocetinostat-induced apoptosis. In an orthotopic xenograft model, we demonstrated that mocetinostat activated miR-31, decreased E2F6, induced apoptosis, and significantly reduced prostate cancer growth. Importantly, we found that mocetinostat also increased miR-31 expression, decreased E2F6, and induced apoptosis in the primary prostate cancer stem cells. Thus, activation of miR-31 and downregulation of E2F6 constitute an important mechanism in mocetinostat-induced apoptosis in prostate cancer.

No MeSH data available.


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Mocetinostat induces apoptosis in prostate cancer cells. DU-145 cells (a) and PC-3 cells (b) were treated with various doses of mocetinostat for 24 h and apoptosis was analyzed using the Cell Death Detection ElisaPLUS kit as described in Materials and Methods. (c) DU-145 cells were treated with various doses of mocetinostat or vorinostat for 72 h. The colonies were fixed with paraformaldehyde and stained with 0.05% crystal violet. All experiments have been repeated three times; data shown are mean values +S.D.
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fig1: Mocetinostat induces apoptosis in prostate cancer cells. DU-145 cells (a) and PC-3 cells (b) were treated with various doses of mocetinostat for 24 h and apoptosis was analyzed using the Cell Death Detection ElisaPLUS kit as described in Materials and Methods. (c) DU-145 cells were treated with various doses of mocetinostat or vorinostat for 72 h. The colonies were fixed with paraformaldehyde and stained with 0.05% crystal violet. All experiments have been repeated three times; data shown are mean values +S.D.

Mentions: We determined whether mocetinostat can induce apoptosis in prostate cancer cells. As shown in Figure 1a, mocetinostat induced significant levels of apoptosis in DU-145 cells in a dose-dependent manner. Induction of apoptosis was determined by the cell death ELISA assay measuring mono- and oligonucleosomes in the lysates of apoptotic cells. Similarly, mocetinostat also induced significant levels of apoptosis in PC-3 cells (Figure 1b). We compared the antitumor activities of mocetinostat and vorinostat (suberanilohydroxamic acid),25 an FDA-approved non-selective HDAC inhibitor. Mocetinostat was significantly more potent than vorinostat in prostate cancer suppression (Figure 1c).


Class I HDAC inhibitor mocetinostat induces apoptosis by activation of miR-31 expression and suppression of E2F6
Mocetinostat induces apoptosis in prostate cancer cells. DU-145 cells (a) and PC-3 cells (b) were treated with various doses of mocetinostat for 24 h and apoptosis was analyzed using the Cell Death Detection ElisaPLUS kit as described in Materials and Methods. (c) DU-145 cells were treated with various doses of mocetinostat or vorinostat for 72 h. The colonies were fixed with paraformaldehyde and stained with 0.05% crystal violet. All experiments have been repeated three times; data shown are mean values +S.D.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4979414&req=5

fig1: Mocetinostat induces apoptosis in prostate cancer cells. DU-145 cells (a) and PC-3 cells (b) were treated with various doses of mocetinostat for 24 h and apoptosis was analyzed using the Cell Death Detection ElisaPLUS kit as described in Materials and Methods. (c) DU-145 cells were treated with various doses of mocetinostat or vorinostat for 72 h. The colonies were fixed with paraformaldehyde and stained with 0.05% crystal violet. All experiments have been repeated three times; data shown are mean values +S.D.
Mentions: We determined whether mocetinostat can induce apoptosis in prostate cancer cells. As shown in Figure 1a, mocetinostat induced significant levels of apoptosis in DU-145 cells in a dose-dependent manner. Induction of apoptosis was determined by the cell death ELISA assay measuring mono- and oligonucleosomes in the lysates of apoptotic cells. Similarly, mocetinostat also induced significant levels of apoptosis in PC-3 cells (Figure 1b). We compared the antitumor activities of mocetinostat and vorinostat (suberanilohydroxamic acid),25 an FDA-approved non-selective HDAC inhibitor. Mocetinostat was significantly more potent than vorinostat in prostate cancer suppression (Figure 1c).

View Article: PubMed Central - PubMed

ABSTRACT

The class I selective inhibitor of the histone deacetylases, mocetinostat, has promising antitumor activities in both preclinical studies and the clinical trials. To understand how mocetinostat induces apoptosis, we examined the effects of mocetinostat on miR-31, a proapoptotic microRNA that was previously found to be epigenetically silenced in prostate cancer. We found that miR-31 was significantly upregulated by mocetinostat in prostate cancer cells. Antiapoptotic protein E2F6, the target of miR-31, was decreased by mocetinostat treatment. When miR-31 was blocked with an inhibitor, the ability of mocetinostat to induce apoptosis was reduced. We further demonstrated that mocetinostat enhanced the activity of docetaxel in apoptosis induction. While siRNA knockdown of E2F6 sensitized cancer cells to mocetinostat-induced apoptosis, overexpression of E2F6 blocked mocetinostat-induced apoptosis. In an orthotopic xenograft model, we demonstrated that mocetinostat activated miR-31, decreased E2F6, induced apoptosis, and significantly reduced prostate cancer growth. Importantly, we found that mocetinostat also increased miR-31 expression, decreased E2F6, and induced apoptosis in the primary prostate cancer stem cells. Thus, activation of miR-31 and downregulation of E2F6 constitute an important mechanism in mocetinostat-induced apoptosis in prostate cancer.

No MeSH data available.


Related in: MedlinePlus