Actin filament formation, reorganization and migration are impaired in hepatic stellate cells under influence of trichostatin A, a histone deacetylase inhibitor

Rombouts, Krista; Knittel, Thomas; Machesky, Laura M.; Braet, Filip; Wielant, Annemie; Hellemans, Karine; Bleser, Pieter De; Gelman, Irwin H.; Ramadori, Giuliano; Geerts, Albert

doi:10.1016/s0168-8278(02)00275-1

Cited by 61 publications

(45 citation statements)

References 59 publications

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“…These data suggest that histone deacetylation, but not DNA methylation, plays a role in v-Srcmediated down-regulation of SSeCKS. This finding agrees with Rombouts et al (34) who showed that TSA could derepress SSeCKS in a model of hepatic injury.…”

Section: Vsr Activity Correlates With Changes In Chromatin Structure-supporting

confidence: 93%

v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex

Gelman

2007

Journal of Biological Chemistry

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SSeCKS (Src-suppressed C kinase substrate), also called gravin/AKAP12, is a large scaffolding protein with metastasis suppressor activity. Two major isoforms of SSeCKS are expressed in most cell and tissue types under the control of two independent promoters, designated ␣ and ␤, separated by 68 kb. SSeCKS transcript and protein levels are severely decreased in Src-and Ras-transformed fibroblasts and in many epithelial tumors. By dissecting its promoters with progressive deletion analysis, we identified the sequence between ؊106 and ؊49 in the ␣ proximal promoter as the minimal v-Src-responsive element, which contains E-and GC-boxes bound by USF1 and Sp1/ Sp3, respectively. Both E-and GC-boxes are crucial for v-Srcresponsive and basal promoter activities. v-Src does not alter USF1 binding levels at the E-box, but it increases Sp1/Sp3 binding to the GC-box despite no change in their cellular protein abundance. SSeCKS ␣ and ␤ transcript levels in v-Src/3T3 cells can be restored by treatment with the histone deacetylase inhibitor, trichostatin A, but not with the DNA demethylation agent, 5-azacytidine. Chromatin changes are found only on the ␣ promoter even though the ␤ proximal promoter contains a similar E-and GC-box arrangement. Recruitment of HDAC1 is necessary and sufficient to cause repression of ␣ proximal promoter activity, and the addition of Sp1 and/or Sp3 potentiates the repression. Our data suggest that suppression of the ␤ promoter is facilitated by Src-induced changes in the ␣ promoter chromatinization mediated by a USF1-Sp1-Sp3 complex.

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Section: Vsr Activity Correlates With Changes In Chromatin Structure-supporting

confidence: 93%

v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex

Gelman

2007

Journal of Biological Chemistry

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“…However, uncontrolled cell proliferation is only a single but not the decisive feature of malignancy. Other effects of aberrant HDAC expression in prostate cancer relevant to tumorigenesis, such as altered cell migration (Rombouts et al, 2002;Klisovic et al, 2005), invasive potential or increased angiogenesis (Kim et al, 2001(Kim et al, , 2004Kwon et al, 2002;Qian et al, 2006) might contribute to the dismal prognosis of patients with HDAC2 high tumours, but this is so far not proven experimentally for this tumour entity. Also, in a multivariate Cox analysis with inclusion of the Ki-67 fraction, HDAC remained an independent prognostic factor, whereas Ki-67 failed significance.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy

Weichert

Roske

Gekeler³

et al. 2008

Br J Cancer

435

314

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High activity of histone deacetylases (HDACs) causes epigenetic alterations associated with malignant cell behaviour. Consequently, HDAC inhibitors have entered late-phase clinical trials as new antineoplastic drugs. However, little is known about expression and function of specific HDAC isoforms in human tumours including prostate cancer. We investigated the expression of class I HDACs in 192 prostate carcinomas by immunohistochemistry and correlated our findings to clinicopathological parameters including follow-up data. Class I HDAC isoforms were strongly expressed in the majority of the cases (HDAC1: 69.8%, HDAC2: 74%, HDAC3: 94.8%). High rates of HDAC1 and HDAC2 expression were significantly associated with tumour dedifferentiation. Strong expression of all HDACs was accompanied by enhanced tumour cell proliferation. In addition, HDAC2 was an independent prognostic marker in our prostate cancer cohort. In conclusion, we showed that the known effects of HDACs on differentiation and proliferation of cancer cells observed in vitro can also be confirmed in vivo. The class I HDAC isoforms 1, 2 and 3 are differentially expressed in prostate cancer, which might be important for upcoming studies on HDAC inhibitors in this tumour entity. Also, the highly significant prognostic value of HDAC2 clearly deserves further study.

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“…1 The involvement of epigenetic regulation during HSC activation was reported in a recent study by Mann et al 9 Treatment of cultured HSCs with a DNA methylation inhibitor prevented the loss of expression of some antifibrotic proteins, such as peroxisome proliferator-activated receptor ␥ and IB␣. Ten years ago, Niki and colleagues 10,11 introduced an HDI as a candidate to preserve a quiescent HSC phenotype in vitro; however, the role of individual HDACs was not addressed, because the broad spectrum inhibitor TSA was used to inhibit the in vitro HSC activation. Because of TSA's limited use in vivo 20,27 we set out to test the influence of the more selective class I HDI VPA 15,16 on the mouse model of CCl 4 -induced liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro, TSA has been shown to inhibit HSC activation, 10,11 whereas in vivo its inhibitory effect on liver fibrosis has never been reported. Because of TSA's limited use in vivo, 20 the influence of the HDI VPA on the mouse model of CCl 4 -induced liver fibrosis was tested because of its preference toward class I HDACs 15,21 and its documented use in mouse models.…”

Section: Vpa Partly Inhibits CCL 4 -Induced Fibrosismentioning

confidence: 99%

Chronic Administration of Valproic Acid Inhibits Activation of Mouse Hepatic Stellate Cells in Vitro and in Vivo

et al. 2010

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Actin filament formation, reorganization and migration are impaired in hepatic stellate cells under influence of trichostatin A, a histone deacetylase inhibitor

Cited by 61 publications

References 59 publications

v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex

v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex

Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy

Chronic Administration of Valproic Acid Inhibits Activation of Mouse Hepatic Stellate Cells in Vitro and in Vivo

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