Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A thorough understanding of histone acetyltransferase CBP/p300-mediated regulation of gene expression and cell growth is essential to identify mechanisms relevant to the development of histone deacetylase (HDAC) inhibitor-based preventive and therapeutic strategies. We found that knockdown of CBP/p300 interacting coactivator with glutamic acid/aspartic acid-rich tail 2 (CITED2) increased colon cancer cell invasiveness in vitro. Gene expression profiling revealed that CITED2 knockdown induced matrix metalloproteinase-13 (MMP-13) gene expression in colon cancer cells. Butyrate, a naturally occurring HDAC inhibitor, induced CITED2 expression and downregulated MMP-13 expression in RKO cells. Additionally, ectopic expression of CITED2 arrested RKO cell growth. Thus, CITED2 regulates colon cancer invasion and might be a target for HDAC inhibitor-based intervention of colon cancer.
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PMID:A role for CITED2, a CBP/p300 interacting protein, in colon cancer cell invasion. 1805 36

Methylation of promoter DNA contributes to transcriptional silencing of various tumor-suppressor genes in cancer. Transcriptional silencing of 15-lipoxygenase-1 (15-LOX-1) promotes tumorigenesis. Methylation of 15-LOX-1 promoter DNA occurs in some cancers, but its mechanistic role in 15-LOX-1 transcriptional silencing is unclear. We examined the mechanistic role of 15-LOX-1 promoter DNA methylation in 15-LOX-1 transcriptional regulation in human colorectal cancers. 15-LOX-1 promoter methylation occurred in colorectal cancer cells in vitro, in 36% of tumor tissue samples of colorectal cancer patients, and in virtually no normal colonic mucosa samples of 50 human subjects with no history of colorectal cancer or polyps. 15-LOX-1 promoter DNA methylation levels, however, did not correlate with 15-LOX-1 expression levels (Spearman's r=0.21; P=0.38). We employed siRNA knockdown and genetic disruption models of DNA methyltransferases (DNMTs) to study the effects of this methylation on 15-LOX-1 expression in colon cancer cells. 15-LOX-1 promoter demethylation was insufficient to reestablish 15-LOX-1 expression. 15-LOX-1 transcription was activated by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) only after DNMT-1 dissociation from the 15-LOX-1 promoter and without altering 15-LOX-1 promoter DNA methylation. DNMT-1 protein hypomorphism impaired DNMT-1 recruitment to the 15-LOX-1 promoter, which allowed 15-LOX-1 transcription activation by SAHA. DNMT-1 has a direct suppressive role in 15-LOX-1 transcriptional silencing that is independent of 15-LOX-1 promoter DNA methylation.
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PMID:15-Lipoxygenase-1 transcriptional silencing by DNA methyltransferase-1 independently of DNA methylation. 1819 15

Decitabine (DAC) and 5-azacitidine have recently been approved for the treatment of myelodysplastic syndrome. The pharmacodynamic effects of DAC and 5-azacitidine outside their known activity as inhibitors of DNA methyltransferases (DNMTs) require further investigation. The purpose of this study was to investigate the effect of DAC on the expression of p21(WAF1/CIP1), a gene with a putative CpG island surrounding its promoter region. Promoter methylation analysis of p21(WAF1/CIP1) in leukemia cells revealed the absence of CpG methylation. However, DAC upregulated p21(WAF1/CIP1) expression in a dose-dependent manner (ED(50)=103.34 nM) and induced G2/M cell cycle arrest in leukemia cells. Sequential application of DAC followed by different histone deacetylase inhibitors induced expression of p21(WAF1/CIP1) synergistically. Upregulation of p21(WAF1/CIP1) paralleled DAC-induced apoptosis (ED(50)=153 nM). Low doses of DAC induced gamma-H2AX expression (ED(50)=16.5 nM) and upregulated p21(WAF1/CIP1) in congenic HCT 116 colon cancer cells in a DNMT-independent and p53-dependent fashion. Inhibition of p53 transactivation by pifithrin-alpha or the kinase activity of ATM by either the specific ATM inhibitor KU-5593 or caffeine abrogated p21(WAF1/CIP1) upregulation, indicating that DAC upregulation of p21(WAF1/CIP1) was p53- and ATM-dependent in leukemia cells. In conclusion, DAC upregulates p21(WAF1/CIP1) in DNMT-independent manner via the DNA damage/ATM/p53 axis.
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PMID:p21(WAF1/CIP1) induction by 5-azacytosine nucleosides requires DNA damage. 1822 91

2D gel electrophoresis is a tool for measuring protein regulation, involving image analysis by dedicated software (PDQuest, Melanie, etc.). Here, partial least squares discriminant analysis was applied to improve the results obtained by classic image analysis and to identify the significant spots responsible for the differences between two datasets. A human colon cancer HCT116 cell line was analyzed, treated and not treated with a new histone deacetylase inhibitor, RC307. The proteins regulated by RC307 were detected by analyzing the total lysates and nuclear proteome profiles. Some of the regulated spots were identified by tandem mass spectrometry. The preliminary data are encouraging and the protein modulation reported is consistent with the antitumoral effect of RC307 on the HCT116 cell line. Partial least squares discriminant analysis coupled with backward elimination variable selection allowed the identification of a larger number of spots than classic PDQuest analysis. Moreover, it allows the achievement of the best performances of the model in terms of prediction and provides therefore more robust and reliable results. From this point of view, the multivariate procedure applied can be considered a good alternative to standard differential analysis, also taking into account the interdependencies existing among the variables.
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PMID:Application of partial least squares discriminant analysis and variable selection procedures: a 2D-PAGE proteomic study. 1822 87

The aim of this work was to obtain the correct classification of a set of two-dimensional polyacrylamide gel electrophoresis map images using the Zernike moments as discriminant variables. For each 2D-PAGE image, the Zernike moments were computed up to a maximum p order of 100. Partial least squares discriminant analysis with variable selection, based on a backward elimination algorithm, was applied to the moments calculated in order to select those that provided the lowest error in cross-validation. The new method was tested on four datasets: (1) samples belonging to neuroblastoma; (2) samples of human lymphoma; (3) samples from pancreatic cancer cells (two cell lines of control and drug-treated cancer cells); (4) samples from colon cancer cells (total lysates and nuclei treated or untreated with a histone deacetylase inhibitor). The results demonstrate that the Zernike moments can be successfully applied for fast classification purposes. The final aim is to build models that can be used to achieve rapid diagnosis of these illnesses.
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PMID:A new method of comparing 2D-PAGE maps based on the computation of Zernike moments and multivariate statistical tools. 1825 13

The histone deacetylase (HDAC) family of transcriptional co-repressors have emerged as important regulators of colon cell maturation and transformation. Pharmacological inhibitors of class I and II HDAC activity (HDACi) are potent inducers of growth arrest, differentiation and apoptosis of colon cancer cells in vitro and in vivo, implicating a role for these HDACs in tumor promotion. Consistent with this role, expression of several HDACs are upregulated in colon tumors, while downregulation of specific HDACs inhibits growth of colon cancer cells in vitro and intestinal tumorigenesis in vivo. This review focuses on the function and transcriptional mechanisms by which class I and II HDACs regulate colon cell maturation and transformation, and on the mechanisms by which HDACi induce growth arrest, differentiation and apoptosis of colon cancer cells. The emerging role of the class III HDAC, Sirt1, in colon cancer progression is also discussed.
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PMID:HDACs and HDAC inhibitors in colon cancer. 1832 39

15-Lipoxygenase-1 (15-LOX-1) contributes significantly to inflammation regulation and terminal cell differentiation. 15-LOX-1 is transcriptionally silenced in cancer cells, and its transcriptional reactivation (e.g. via histone deacetylase inhibitors (HDACIs)) is essential for restoring terminal cell differentiation to cancer cells. STAT-6 acetylation via the histone acetyltransferase KAT3B has been proposed to be necessary for 15-LOX-1 transcriptional activation. However, the exact mechanism underlying 15-LOX-1 transcriptional reactivation in cancer cells is still undefined, especially in regard to the contribution of 15-LOX-1 promoter histone modifications. We therefore examined the relative mechanistic contributions of 15-LOX-1 promoter histone modifications and STAT-6 to 15-LOX-1 transcriptional reactivation by HDACIs in colon cancer cells. We found that: 1) histone H3 and H4 acetylation in the 15-LOX-1 promoter through KAT3B was critical to 15-LOX-1 transcriptional activation; 2) 15-LOX-1 transcription was activated independently from STAT-6; and 3) dimethyl-histone H3 lysine 9 (H3K9me2) demethylation in the 15-LOX-1 promoter via the histone lysine demethylase KDM3A was an early and specific histone modification and was necessary for activation of transcription. These findings demonstrate that histone modification in the 15-LOX-1 promoter is important to 15-LOX-1 transcriptional silencing in colon cancer cells and that HDACIs can activate gene transcription via KDM3A demethylation of H3K9me2.
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PMID:Chromatin modification requirements for 15-lipoxygenase-1 transcriptional reactivation in colon cancer cells. 1879 63

Systemic sclerosis (SSc) is characterized by immunological abnormalities, especially the production of autoantibodies against various cellular components. Treatment with histone deacetylase (HDAC) inhibitors prevents collagen accumulation in a mouse SSc model. Additionally, autoantibody against HDAC-3 is produced in colon cancer patients, while HDAC-1 and HDAC-2 do not elicit autoantibody response. To determine the presence and levels of antibodies (Abs) against HDAC-3 in SSc. Anti-HDAC-3 Ab was examined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting using human recombinant HDAC-3. The HDAC-3 activity was evaluated by ELISA using the fluorimetric HDAC lysyl substrate that comprises an acetylated lysine side chain. Contrary to our hypothesis that autoimmune background in SSc induced the production of autoantibody against HDACs, IgG and IgM anti-HDAC-3 Ab levels in SSc patients were significantly lower than in normal controls (p < 0.0005 and 0.001, respectively). Furthermore, decreased levels of IgG anti-HDAC-3 Ab were specific to SSc, since IgG anti-HDAC-3 Ab levels in patients with dermatomyositis (DM) and those with systemic lupus erythematosus (SLE) were similar and slightly increased relative to normal controls, respectively. Immunoblotting analysis showed that anti-HDAC-3 Ab was detected in normal controls and patients with DM or SLE, while it was absent in SSc patients. The HDAC-3 activity was significantly inhibited by IgG isolated from sera of normal controls, whereas such inhibitory effect was not observed by IgG isolated from sera of SSc patients. These results indicate the lack of anti-HDAC-3 autoantibody in SSc patients, which is produced in healthy individuals as well as DM and SLE patients, suggesting that this autoantibody might function as protective Ab.
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PMID:Decreased levels of autoantibody against histone deacetylase 3 in patients with systemic sclerosis. 1902 Oct 12

Unbalanced histone deacetylase (HDAC) hyperactivity is a common feature of tumor cells. Inhibition of HDAC activity is often associated with cancer cell growth impairment and death. Valproic acid (VPA) is a HDAC inhibitor used for the treatment of epilepsy. It has recently been recognized as a promising anticancer drug. We investigated the effects of VPA on growth and survival of colon cancer cells. VPA caused growth inhibition and programmed cell death that correlated with histone hyperacetylation. VPA modulated the expression of various factors involved in cell cycle control and apoptosis and induced caspase activation. Interestingly, VPA induced downregulation of c-Src and potentiated the cytotoxic effects of the c-Src inhibitor bosutinib, both in vitro and in vivo. The combination of sublethal doses of VPA and bosutinib led to massive apoptosis of colon cancer cells, irrespective of their genetic background. These results suggest that VPA may be employed as a positive modulator of bosutinib antitumor activity in colorectal cancer.
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PMID:Valproic acid enhances bosutinib cytotoxicity in colon cancer cells. 1912 74

Despite the availability of several Food and Drug Administration-approved drugs, advanced inoperable colorectal cancer remains incurable. In this study, we focused on the development of combined molecular targeted therapies against colon cancer by testing the efficacy of the combination of the histone deacetylase inhibitor vorinostat with the proteasome inhibitor bortezomib to determine if this resulted in synergistic antitumor effects against colorectal cancer. The effects of the histone deacetylase inhibitor vorinostat in combination with the proteasome inhibitor bortezomib on the growth of two colorectal cancer cell lines were assessed with regard to proliferation, cell cycle arrest, and apoptosis. Treatment with the combination of vorinostat and bortezomib resulted in a synergistic decrease in proliferation of both colorectal cancer cell lines compared with treatment with single agents alone. This inhibition was associated with a synergistic increase in apoptosis as measured by caspase-3/7 activity and cleaved poly(ADP-ribose) polymerase. In addition, we observed an increase in the proapoptotic protein BIM and in the number of cells arrested in the G(2)-M phase of the cell cycle. Although p21 levels were significantly increased, short hairpin RNA knockdown of p21 did not lead to changes in proliferation in response to the combination of drugs, indicating that although p21 is a target of these drugs, it is not required to mediate their antiproliferative effects. These data indicate that combination treatment with vorinostat and bortezomib result in synergistic antiproliferative and proapoptotic effects against colon cancer cell lines, providing a rational basis for the clinical use of this combination for the treatment of colorectal cancer.
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PMID:Vorinostat and bortezomib exert synergistic antiproliferative and proapoptotic effects in colon cancer cell models. 1917 60


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