Effect of trichostatin A on cell growth and expression of cell cycle- and apoptosis-related molecules in human gastric and oral carcinoma cell lines

Suzuki, Tetsuo; Yokozaki, Hiroshi; Kuniyasu, Hiroki; Hayashi, Ken; Naka, Kazuhito; Ono, Shigehiro; Ishikawa, Takenori; Tahara, Eiichi; Yasui, Wataru

doi:10.1002/1097-0215(20001215)88:6<992::aid-ijc24>3.0.co;2-9

Cited by 114 publications

(82 citation statements)

References 17 publications

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“…Inhibition of HDAC activity is known to revert the phenotype of transformed cells (13,14) into nontransformed phenotypes (2,13,14). Since the most clearly changed characteristic is an alteration of cytoskeletal organization, we investigated whether TSA regulates the functions of proteins involved in cytoskeletal organization.…”

Section: Detransformation Of Ras-transformed Fibroblasts By Tsa-mentioning

confidence: 99%

“…Recently, it has been shown that inhibition of HDAC activity by TSA is able to revert the morphological changes seen following the transformation of cells in culture with v-sis and v-ras oncogenes (12). TSA-treated cells become more flattened and have well organized actin stress fibers (13,14). Therefore, TSA has an ability to detransform at least ras-transformed fibroblasts.…”

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confidence: 99%

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Trichostatin A-induced Detransformation Correlates with Decreased Focal Adhesion Kinase Phosphorylation at Tyrosine 861 in ras-transformed Fibroblasts

Lim

Han

Kwon

et al. 2002

Journal of Biological Chemistry

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To elucidate the role of focal adhesion kinase (pp125FAK) in transformation, its phosphorylation in transformed fibroblasts was compared with that of detransformed fibroblasts induced by a histone deacetylase inhibitor, trichostatin A (TSA). Inhibition of histone deacetylase activity in two different ras-transformed fibroblast lines by TSA induced a morphological change into a flattened and more spread morphology, implying detransformation. These morphological changes included increased spreading ability of transformed NIH 3T3 cells on fibronectin. Of the six tyrosine phosphorylation sites in pp125FAK, phosphorylation at position 861 (Tyr-861) was clearly decreased during detransformation by TSA. It resulted from decreased activity of Src family tyrosine kinase and/or decreased amount of Src kinase interacting with pp125FAK. Furthermore, phosphorylation of Tyr-861 was reduced substantially by the Src family kinase inhibitor, PP1, while overexpression of Src kinase increased its phosphorylation, implying that Src kinase regulates phosphorylation of pp125FAK at Tyr-861. All of these findings suggest that increased phosphorylation of pp125FAK at Tyr-861 correlates with Ras-induced transformation of fibroblasts, and TSA is able to detransform them through regulation of pp125FAK phosphorylation at Tyr-861 by an Src family kinase.

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Section: Detransformation Of Ras-transformed Fibroblasts By Tsa-mentioning

confidence: 99%

mentioning

confidence: 99%

Trichostatin A-induced Detransformation Correlates with Decreased Focal Adhesion Kinase Phosphorylation at Tyrosine 861 in ras-transformed Fibroblasts

Lim

Han

Kwon

et al. 2002

Journal of Biological Chemistry

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“…In addition, the natural product HDACIs of the trapoxin class and trichostatin were shown to activate the p21 promoter, increase p21 protein levels, inhibit cyclin-dependent kinase 2 kinase activity, reduce retinoblastoma (Rb) phosphorylation, and cause cell cycle arrest or apoptosis in three human tumor cell lines (21,28,29). NVP-LAQ824, our novel synthetic HDACI, showed similar properties at submicromolar concentrations.…”

Section: Introductionmentioning

confidence: 96%

“…Cell proliferation was measured using an adaptation of published procedures (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfonyl)-2H-tetrazolium assay) as described previously (29). The CellTiter 96 AQueous Non-Radioactive Cell Proliferation Assay was performed according to the manufacturer's protocol.…”

Section: Introductionmentioning

confidence: 99%

Selective Growth Inhibition of Tumor Cells by a Novel Histone Deacetylase Inhibitor, NVP-LAQ824

et al. 2004

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We have synthesized a histone deacetylase inhibitor, NVP-LAQ824, a cinnamic hydroxamic acid, that inhibited in vitro enzymatic activities and transcriptionally activated the p21 promoter in reporter gene assays. NVP-LAQ824 selectively inhibited growth of cancer cell lines at submicromolar levels after 48 -72 h of exposure, whereas higher concentrations and longer exposure times were required to retard the growth of normal dermal human fibroblasts. Flow cytometry studies revealed that both tumor and normal cells arrested in the G 2 -M phase of the cell cycle after compound treatment. However, an increased sub-G 1 population at 48 h (reminiscent of apoptotic cells) was observed only in the cancer cell line. Annexin V staining data supported our hypothesis that NVP-LAQ824 induced apoptosis in tumor and transformed cells but not in normal cells. Western blotting experiments showed an increased histone H3 and H4 acetylation level in NVP-LAQ824-treated cancer cells, suggesting that the likely in vivo target of NVP-LAQ824 was histone deacetylase(s). Finally, NVP-LAQ824 exhibited antitumor effects in a xenograft animal model. Together, our data indicated that the activity of NVP-LAQ824 was consistent with its intended mechanism of action. This novel histone deacetylase inhibitor is currently in clinical trials as an anticancer agent.

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“…Histone hyperacetylation is thought to relax the chromatin structure and allow transcription factors to access promoters (Luger et al, 1997;Luger and Richmond, 1998). We have reported that trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, induces expression of p21 Waf1 and HLTF in GC cell lines (Suzuki et al, 2000;Hamai et al, 2003). HDACs are separated into three distinct classes on the basis of their homologies to yeast transcriptional repressors (North et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Loss of heterozygosity and histone hypoacetylation of the PINX1 gene are associated with reduced expression in gastric carcinoma

et al. 2005

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The expression of PINX1, a possible telomerase inhibitor and a putative tumor suppressor, has not been studied in human cancers, including gastric cancer (GC). We examined expression of PINX1 by quantitative reverse transcription (RT)-PCR in 73 cases of GC, and 45 of these cases were further studied for loss of heterozygosity (LOH) by PCR with microsatellite marker D8S277. Reduced expression (tumor vs normal ratioo0.5) of PINX1 was detected in 50 (68.5%) of 73 cases of GC. GC tissues with reduced expression of PINX1 showed significantly higher telomerase activities as measured by telomeric repeat amplification protocol than those with normal expression of PINX1 (P ¼ 0.031). LOH of PINX1 locus was detected in 15 (33.3%) of 45 cases of GC and was correlated significantly with reduced expression of PINX1 (P ¼ 0.031). Expression of PINX1 in a GC cell line, MKN-74, was induced by treatment with trichostatin A (TSA) or nicotinamide (NAM). Chromatin immunoprecipitation assay of MKN-74 cells revealed that acetylation of histone H4 in the 5 0 untranslated region (UTR) of PINX1 was enhanced by treatment with TSA or NAM, whereas acetylation of histone H3 was not changed by TSA or NAM. In addition, TSA or NAM treatment led to inhibition of telomerase activity in MKN-74 cells. These results indicate that LOH of PINX1 locus and hypoacetylation of histone H4 in the 5 0 UTR of PINX1 are associated with reduced expression of PINX1 in GC.

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Effect of trichostatin A on cell growth and expression of cell cycle- and apoptosis-related molecules in human gastric and oral carcinoma cell lines

Cited by 114 publications

References 17 publications

Trichostatin A-induced Detransformation Correlates with Decreased Focal Adhesion Kinase Phosphorylation at Tyrosine 861 in ras-transformed Fibroblasts

Trichostatin A-induced Detransformation Correlates with Decreased Focal Adhesion Kinase Phosphorylation at Tyrosine 861 in ras-transformed Fibroblasts

Selective Growth Inhibition of Tumor Cells by a Novel Histone Deacetylase Inhibitor, NVP-LAQ824

Loss of heterozygosity and histone hypoacetylation of the PINX1 gene are associated with reduced expression in gastric carcinoma

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