Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes

Kim, Myoung Sook; Kwon, Ho Jeong; Lee, You Mie; Baek, Jin Hyen; Jang, Jae Eun; Lee, Sae Won; Moon, Eun Joung; Kim, Hae Sun; Lee, Seok Ki; Chung, Hae Young; Kim, Chul Woo; Kim, Kyu Won

doi:10.1038/86507

Cited by 684 publications

(551 citation statements)

References 38 publications

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“…Supporting our idea, specific HDAC inhibitors have been shown to inhibit angiogenesis [31,32], although little has been known about the mechanism of HDAC inhibitor in anti-angiogenesis until now. HDAC inhibitor should undergo further examination not only as an anti-angiogenesis agent, but also regarding its role in maspin re-expression to explore its potential as a possible biomarker for relapse risk in cancer therapy, as alterations in maspin expression are known to play an important role in oral tumorigenesis.…”

Section: Discussionmentioning

confidence: 83%

Effects of demethylating agent 5-aza-2′-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

Murakami¹,

Asaumi²,

Maki³

et al. 2004

Oral Oncology

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Summary Maspin, which belongs to the serine protease inhibitor (serpin) superfamily, has been proposed as a potent tumor suppressor that inhibits cell motility, invasion, angiogenesis, and metastasis. In the present study, we examined the effects of 5-Aza-2'-deoxycytidine (5-Aza-dC), a demethylating agent, and FR901228, a histone deacetylase (HDAC) inhibitor, on maspin expression in oral cancer cell lines. The expression levels of maspin mRNA were divided into two groups, which was the maspin low-expressed and high-expressed cell lines in the 12 oral cancer cell lines. The maspin promoter contained only a few methylated CpG sites in the maspin low-expressed cell lines. Moreover, the methylation status was not altered after 5Aza-dC treatment. However, the transcription of the maspin gene was clearly increased following 5Aza-dC treatment in a number of oral cancer cell lines. These results imply that an action of 5Aza-dC is separate from induction of promoter demethylation. Treatment with FR901228 resulted in a time-dependent stimulation of the re-expression of maspin mRNA as early as 4 hours after treatment in the maspin downregulated cells. The re-expression of the maspin gene may contribute to the recuperation of biological functions linked to FR901228 such as an inhibitory effect on tumor angiogenesis and cell invasion. These results indicate that maspin and its target genes may be excellent leads for future studies on the potential benefits of FR901228, a histone deacetylase inhibitor, in cancer therapy.

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Section: Discussionmentioning

confidence: 83%

Effects of demethylating agent 5-aza-2′-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

Murakami¹,

Asaumi²,

Maki³

et al. 2004

Oral Oncology

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“…This dependence appears to vary with the agent used and may be due to differences in potency. 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].…”

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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“…The HDAC-inhibitor TSA blocks class I and II HDACs leading to alterations in chromatin structure that modulate gene expression (24). TSA has been shown to inhibit hypoxia-and VEGF induced angiogenesis (25)(26)(27). In vivo, it is a potent inhibitor of angiogenesis as it reduces neo-vessel formation in the CAM-assay and inhibits bFGFinduced angiogenesis in the Matrigel-plug assay in mice.…”

Section: Dose-response Experiments With Screening Hitsmentioning

confidence: 99%

A novel imaging‐based high‐throughput screening approach to anti‐angiogenic drug discovery

et al. 2009

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The successful progression to the clinic of angiogenesis inhibitors for cancer treatment has spurred interest in developing new classes of anti-angiogenic compounds. The resulting surge in available candidate therapeutics highlights the need for robust, highthroughput angiogenesis screening systems that adequately capture the complexity of new vessel formation while providing quantitative evaluation of the potency of these agents. Available in vitro angiogenesis assays are either cumbersome, impeding adaptation to high-throughput screening formats, or inadequately model the complex multistep process of new vessel formation. We therefore developed an organotypic endothelial-mural cell co-culture assay system that reflects several facets of angiogenesis while remaining compatible with high-throughput/high-content image screening. Co-culture of primary human endothelial cells (EC) and vascular smooth muscle cells (vSMC) results in assembly of a network of tubular endothelial structures enveloped with vascular basement membrane proteins, thus, comprising the three main components of blood vessels. Initially, EC are dependent on vSMC-derived VEGF and sensitive to clinical anti-angiogenic therapeutics. A subsequent phenotypic VEGFswitch renders EC networks resistant to anti-VEGF therapeutics, demarcating a mature vascular phenotype. Conversely, mature EC networks remain sensitive to vascular disrupting agents. Therefore, candidate anti-angiogenic compounds can be interrogated for their relative potency on immature and mature networks and classified as either vascular normalizing or vascular disrupting agents. Here, we demonstrate that the EC-vSMC co-culture assay represents a robust high-content imaging high-throughput screening system for identification of novel anti-angiogenic agents. A pilot highthroughput screening campaign was used to define informative imaging parameters and develop a follow-up dose-response scheme for hit characterization. High-throughput screening using the EC-vSMC co-culture assay establishes a new platform to screen for novel anti-angiogenic compounds for cancer therapy. ' 2009 International Society for Advancement of Cytometry Key termshigh-throughput screening; endothelial/mural cell co-culture; angiogenesis INHIBITING angiogenesis is a validated therapeutic modality for cancer (1). Hence, new agents that potently inhibit pathological angiogenesis are a critical component of future combination cancer therapies (2). The identification of candidate therapeutics relies on current in vitro angiogenesis assays that measure effects on endothelial cell migration, proliferation, apoptosis and tube formation, and in vivo models such as the chick chorioallantoic membrane assay, corneal neovascularization assay, and Matrigel plug assays (3-5). Current in vitro angiogenesis assays are generally focused on specific behaviors of monocultured endothelial cells (EC) (e.g., migration, proliferation) and fail to model heterotypic perivascular interactions, whereas in vivo systems are not compatible ...

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Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes

Cited by 684 publications

References 38 publications

Effects of demethylating agent 5-aza-2′-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

Effects of demethylating agent 5-aza-2′-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

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

A novel imaging‐based high‐throughput screening approach to anti‐angiogenic drug discovery

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