Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim

Zhao, Yan; Tan, Jian; Li, Zhuang; Jiang, Xia; Liu, Edison T.; Q, Yu

doi:10.1073/pnas.0505585102

Cited by 224 publications

(208 citation statements)

References 55 publications

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“…25,26 E2F-1 differs from that of other E2F family members due to its ability to regulate not only cell-cycle progression but also apoptosis as it directly induces the expression of p73, of caspase 3 and 7 and of some pro-apoptotic Bcl-2 family members. [27][28][29][30][31][32][33][34] We show here that E2F-1 is a major contributor of caspase-dependent induction of Noxa in response to ABT-737 treatment. Caspases cleave the E2F-1 regulator pRb in ABT-737-treated cells, giving rise to a p68Rb truncated form, which has a direct role in Noxa and cell death inductions together with E2F-1.…”

mentioning

confidence: 50%

pRb/E2F-1-mediated caspase-dependent induction of Noxa amplifies the apoptotic effects of the Bcl-2/Bcl-xL inhibitor ABT-737

et al. 2013

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Although Bcl-2 family members control caspase activity by regulating mitochondrial permeability, caspases can, in turn, amplify the apoptotic process upstream of mitochondria by ill-characterized mechanisms. We herein show that treatment with a potent inhibitor of Bcl-2 and Bcl-xL, ABT-737, triggers caspase-dependent induction of the BH3-only protein, Mcl-1 inhibitor, Noxa. RNA interference experiments reveal that induction of Noxa, and subsequent cell death, rely not only on the transcription factor E2F-1 but also on its regulator pRb. In response to ABT-737, pRb is cleaved by caspases into a p68Rb form that still interacts with E2F-1. Moreover, pRb occupies the noxa promoter together with E2F-1, in a caspase-dependent manner upon ABT-737 treatment. Thus, caspases contribute to trigger the mitochondrial apoptotic pathway by coupling Bcl-2/Bcl-xL inhibition to that of Mcl-1, via the pRb/E2F-1-dependent induction of Noxa.

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confidence: 50%

pRb/E2F-1-mediated caspase-dependent induction of Noxa amplifies the apoptotic effects of the Bcl-2/Bcl-xL inhibitor ABT-737

et al. 2013

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“…Furthermore, acetylation of p53 occurs following HDAC inhibitor administration and may increase its activity and reduce targeting of p53 for degradation [22,39,40]. However, others have shown HDAC inhibitors to have apoptotic effects independent from p53 [41]. More experiments are required to define the expression, mutation, and role of p53 in HDAC inhibitor-mediated apoptosis of Ark2 cells.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells

Jiang

Dowdy

Meng

et al. 2007

Gynecologic Oncology

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Objective-To characterize the molecular pathways involved in apoptosis following administration of histone deacetylase inhibitors to Type I and II endometrial cancer cells.Methods-Ark2, Ishikawa, and AN3 cell lines representing both Type I and II endometrial cancers were treated with various concentrations of oxamflatin and HDAC inhibitor-1. Cell apoptosis was determined by flow cytometry, nuclear staining, Western blotting, and mitochondrial membrane potential assays.Results-Compared to controls, there was a 95% reduction in the growth of Ark2 cells following administration of histone deacetylase inhibitors and this response was dose-dependent. These agents also caused profound morphologic changes and loss of mitochondrial membrane potentials consistent with the induction of apoptosis. Cleavage of PARP, caspase-9, and caspase-8 was detected, confirming the activation of apoptotic cascades in endometrial carcinoma cells. This effect was present in both serous and endometrioid cell types.Conclusion-Our results suggest that oxamflatin and HDAC inhibitor-1 have potent cytotoxicity in endometrial cancer cells by inducing cell apoptosis. Histone deacetylase inhibitors are promising agents for the treatment of both Type I and II endometrial carcinoma.

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“…19,20 Trichostatin A (TSA) is a natural HDACi that promotes histone hyperacetylation and strongly induces apoptosis by altering the expression of some apoptotic genes. [21][22][23] However, it was also reported to show relatively modest antitumor activity in cases of head and neck squamous cell carcinoma (SCC) cells. The limited effect of TSA was associated with NF-kB's activation by this HDACi.…”

Section: Introductionmentioning

confidence: 99%

The effects of trichostatin A on the oncolytic ability of herpes simplex virus for oral squamous cell carcinoma cells

et al. 2008

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Combining the use of a chemotherapeutic agent with oncolytic virotherapy is a useful way to increase the efficiency of the treatment of cancer. The effect of the histone diacetylase (HDAC) inhibitor trichostatin A (TSA) on the antitumor activity of a herpes simplex virus type-1 (HSV-1) mutant was examined in oral squamous cell carcinoma (SCC) cells. Immunoblotting analysis and immunoflourescence staining revealed that a cytoplasmic nuclear factor-kB (NF-kB) component, p65, translocated into the nucleus after infection with g 1 34.5 gene-deficient HSV-1 R849, indicating that R849 activated NF-kB. TSA induced acetylation of p65 and increased the amount of p65 in the nucleus of oral SCC cells. Treatment of R849-infected cells with TSA also increased the amount of nuclear p65 and binding of NF-kB to its DNA-binding site and an NF-kB inhibitor SN50 diminished the increase in nuclear p65. In the presence of TSA, the production of virus and the expression of LacZ integrated into R849 and glycoprotein D, but not ICP0, ICP6 and thymidine kinase, were increased. The viability of cells treated with a combination of R849 and TSA was lower than that of those treated with R849 only. After treatment with TSA, expression of the cell cycle kinase inhibitor p21 was upregulated and the cell cycle was arrested at G1. These results indicate that TSA enhanced the replication of the HSV-1 mutant through the activation of NF-kB and induced cell cycle arrest at G1 to inhibit cell growth. TSA can be used as an enhancing agent for oncolytic virotherapy for oral SCC with g 1 34.5 gene-deficient HSV-1.

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Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim

Cited by 224 publications

References 55 publications

pRb/E2F-1-mediated caspase-dependent induction of Noxa amplifies the apoptotic effects of the Bcl-2/Bcl-xL inhibitor ABT-737

pRb/E2F-1-mediated caspase-dependent induction of Noxa amplifies the apoptotic effects of the Bcl-2/Bcl-xL inhibitor ABT-737

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells

The effects of trichostatin A on the oncolytic ability of herpes simplex virus for oral squamous cell carcinoma cells

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