Trichostatin A Induces Morphological Changes and Gelsolin Expression by Inhibiting Histone Deacetylase in Human Carcinoma Cell Lines

Hoshikawa, Yutaka; Kwon, Ho Jeong; Yoshida, Minoru; Horinouchi, Sueharu; Beppu, Teruhiko

doi:10.1006/excr.1994.1248

Cited by 178 publications

(124 citation statements)

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“…We showed that de novo protein synthesis is required for the morphological changes of HeLa cells (Figure 3b). We previously showed that TSA caused enhanced expression of gelsolin, an actin regulatory protein (Hoshikawa et al, 1994). In this study, we also showed that oxam¯atin caused a marked increase in gelsolin.…”

Section: Discussionsupporting

confidence: 75%

“…During the experiments of in vitro cytotoxicity described above, we found that oxam¯atin induced the morphological changes of human cell lines characteristic of cells treated with TSA and other HDAC inhibitors (Hoshikawa et al, 1994). Figure 3 shows the morphological changes of HeLa cells treated with oxam¯atin as well as TSA.…”

Section: E Ects Of Oxam¯atin On the Cell Morphology Of Hela Cellsmentioning

confidence: 95%

“…These morphological changes were apparently similar to those of TSA-treated cells (Figure 3a). The morphological changes induced by TSA required de novo transcription and translation (Hoshikawa et al, 1994). We therefore examined whether protein and RNA synthesis inhibitors a ect the oxam¯atin-induced morphological changes (Figure 3b).…”

Section: E Ects Of Oxam¯atin On the Cell Morphology Of Hela Cellsmentioning

confidence: 99%

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Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

et al. 1999

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Oxam¯atin [(2E) -5 -[3 -[(phenylsufonyl) amino] phenyl]-pent-2-en-4-ynohydroxamic acid] induces transcriptional activation of junD and morphological reversion in various NIH3T3-derived transformed cell lines. We found that oxam¯atin showed in vitro antiproliferative activity against various mouse and human tumor cell lines with drastic changes in the cell morphology and in vivo antitumor activity against B16 melanoma. Oxam¯atin caused an elongated cell shape with ®lamentous protrusions as well as arrest of the cell cycle at the G1 phase in HeLa cells. These phenotypic changes of HeLa cells were apparently similar to those by trichostatin A (TSA), a speci®c inhibitor of histone deacetylase (HDAC). The e ect of oxam¯atin on the transcriptional activity of the cytomegalovirus (CMV) promoter was examined and compared with known HDAC inhibitors, TSA, sodium n-butyrate, and FR901228. Oxam¯atin as well as all these inhibitors greatly enhanced the transcriptional activity of the CMV promoter in a dose-dependent manner. Oxam¯atin, like TSA, inhibited intracellular HDAC activity, as a result of which marked amounts of acetylated histone species accumulated. Finally, e ects on expression of several endogenous genes involved in cell morphology and cell cycle control in HeLa cells were analysed. Expression of gelsolin, cyclin E and Cdk inhibitors including p21 WAF1/Cip1 was highly augmented, while that of cyclin A and cyclin D1 was decreased by oxam¯atin. These results suggest that changes in the expression pattern of the genes regulating cell morphology and the cell cycle due to histone hyperacetylation are responsible for the antitumor activity, the morphological change and the cell cycle arrest induced by oxam¯atin.

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Section: Discussionsupporting

confidence: 75%

Section: E Ects Of Oxam¯atin On the Cell Morphology Of Hela Cellsmentioning

confidence: 95%

Section: E Ects Of Oxam¯atin On the Cell Morphology Of Hela Cellsmentioning

confidence: 99%

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Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

et al. 1999

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“…The morphology of the bladder carcinoma cell line T24 dramatically changed, and actin stress fibers reappeared during treatment with TSA. 14 It was shown that incubation with TSA resulted in a dramatic upregulation of gelsolin RNA and protein levels that preceded apoptotic death of breast cancer cell lines. 30 Recently, Dong et al 31 demonstrated the presence of a ciselement defined as a 27 bp sequence located approximately Ϫ135 bp upstream of the transcription start site that mediated gelsolin gene silencing.…”

Section: Discussionmentioning

confidence: 99%

“…13 Histone deacetylase (HDAC) inhibitors, such as trichostatin A (TSA) and apicidin, selectively induced the expression of gelsolin. 14,15 Recent studies have suggested a new mechanism for cell-specific gene regulation linking nuclear architecture, chromatin structure and functional organization of DNA sequences. 16 In an effort to determine the molecular basis of gelsolin downregulation in urinary bladder cancer and to better understand the carcinogenic process, we investigated the gelsolin promoter through the use of methylation-specific sequencing, luciferase assays and chromatin immunoprecipitation (ChIP) assays.…”

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Gelsolin gene silencing involving unusual hypersensitivities to dimethylsulfate and KMnO₄in vivo footprinting on its promoter region

Haga

Fujita

Nomoto

et al. 2004

Intl Journal of Cancer

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We previously reported that gelsolin gene expression is reduced in various tumors. In an effort to gain further insights into the mechanism of gelsolin downregulation in tumors, we examined the in vivo properties of the gelsolin promoter in urinary bladder cancer cell lines. Neither mutation nor hypermethylation was responsible for gene silencing at the promoter. After exposure to trichostatin A (TSA), a histone deacetylase inhibitor, gelsolin promoter activity was markedly enhanced in the cancer cells, not in cells derived from normal tissue. Chromatin immunoprecipitation assays revealed that both histones H3 and H4 were hypoacetylated in the promoter region of the cancer cells, and the accumulation of acetylated histones was detected by TSA treatment. Key words: gelsolin; gene silencing; dimethylsulfate hypersensitivity; bladder cancer; in vivo footprintingCancers occur due to the accumulation of abnormalities in gene function. While many of them are genetic (mutation and deletion), epigenetically mediated changes in gene expression have been increasingly investigated. Hypermethylation of CpG islands, which are GC-rich regions usually located at the 5Ј end of genes, results in alterations in the histone acetylation and methylation status around gene promoter regions. Aberrant cytosine methylation and concomitant histone modifications play important roles in the repression of over half of the tumor suppressor genes during malignant transformation. 1,2Previously, we reported that the expression of gelsolin, an actin-regulatory protein, is frequently silenced in various cancers, including stomach, colon, urinary bladder and lung, and that gelsolin functions as a tumor suppressor. [3][4][5][6][7] These findings were also demonstrated in breast and prostate cancers. 8,9 On the other hand, a subset of non small cell lung cancers is characterized by high expression levels of gelsolin correlated with lymphatic invasion, 10 and there was a gradual increase in gelsolin with an increase in tumor grade and stage in uroepithelial carcinoma. 11 Gelsolin induced invasion of epithelial cells as well as colon adenocarcinoma cells. 12 It is therefore possible that a decrease in expression during a particular stage is followed by an increase during another stage. To understand roles of gelsolin in the whole process of tumorigenesis, mechanisms for both down-and upregulations should be analyzed. In breast cancers, gelsolin genes were not mutated; however, epigenetic changes in the chromatin structure were responsible for the deficiency. 13 Histone deacetylase (HDAC) inhibitors, such as trichostatin A (TSA) and apicidin, selectively induced the expression of gelsolin. 14,15 Recent studies have suggested a new mechanism for cell-specific gene regulation linking nuclear architecture, chromatin structure and functional organization of DNA sequences. 16 In an effort to determine the molecular basis of gelsolin downregulation in urinary bladder cancer and to better understand the carcinogenic process, we investigated the gelsolin prom...

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Non‐Genotoxic Causes of Cancer

Murphy

Jirtle

2005

The Cancer Handbook

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Trichostatin A Induces Morphological Changes and Gelsolin Expression by Inhibiting Histone Deacetylase in Human Carcinoma Cell Lines

Cited by 178 publications

References 0 publications

Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

Gelsolin gene silencing involving unusual hypersensitivities to dimethylsulfate and KMnO₄in vivo footprinting on its promoter region

Non‐Genotoxic Causes of Cancer

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Trichostatin A Induces Morphological Changes and Gelsolin Expression by Inhibiting Histone Deacetylase in Human Carcinoma Cell Lines

Cited by 178 publications

References 0 publications

Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

Gelsolin gene silencing involving unusual hypersensitivities to dimethylsulfate and KMnO4in vivo footprinting on its promoter region

Non‐Genotoxic Causes of Cancer

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Gelsolin gene silencing involving unusual hypersensitivities to dimethylsulfate and KMnO₄in vivo footprinting on its promoter region