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)

Histone deacetylase 3 (HDAC3) is overexpressed in approximately half of all colon adenocarcinomas. We took an RNAi approach to determine how HDAC3 influenced chromatin modifications and the expression of growth regulatory genes in colon cancer cells. A survey of histone modifications revealed that HDAC3 knockdown in SW480 cells significantly increased histone H4-K12 acetylation, a modification present during chromatin assembly that has been implicated in imprinting. This modification was found to be most prominent in proliferating cells in the intestinal crypt and in APC(Min) tumors, but was less pronounced in the tumors that overexpress HDAC3. Gene expression profiling of SW480 revealed that HDAC3 shRNA impacted the expression of genes in the Wnt and vitamin D signaling pathways. The impact of HDAC3 on Wnt signaling was complex, with both positive and negative effects observed. However, long-term knockdown of HDAC3 suppressed beta-catenin translocation from the plasma membrane to the nucleus, and increased expression of Wnt inhibitors TLE1, TLE4 and SMO. HDAC3 knockdown also enhanced expression of the TLE1 and TLE4 repressors in HT-29 and HCT116 cells. HDAC3 shRNA enhanced expression of the vitamin D receptor in SW480 and HCT116 cells, and rendered SW480 cells sensitive to 1,25-dihydroxyvitamin D3. We propose that HDAC3 overexpression alters the epigenetic programming of colon cancer cells to impact intracellular Wnt signaling and their sensitivity to external growth regulation by vitamin D.
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PMID:HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signaling. 1878 8

Human colon cancer cells and primary colon cancer silence the gene coding for LDH (lactate dehydrogenase)-B and up-regulate the gene coding for LDH-A, resulting in effective conversion of pyruvate into lactate. This is associated with markedly reduced levels of pyruvate in cancer cells compared with non-malignant cells. The silencing of LDH-B in cancer cells occurs via DNA methylation, with involvement of the DNMTs (DNA methyltransferases) DNMT1 and DNMT3b. Colon cancer is also associated with the expression of pyruvate kinase M2, a splice variant with low catalytic activity. We have shown recently that pyruvate is an inhibitor of HDACs (histone deacetylases). Here we show that pyruvate is a specific inhibitor of HDAC1 and HDAC3. Lactate has no effect on any of the HDACs examined. Colon cancer cells exhibit increased HDAC activity compared with non-malignant cells. HDAC1 and HDAC3 are up-regulated in colon cancer cells and in primary colon cancer, and siRNA (small interfering RNA)-mediated silencing of HDAC1 and HDAC3 in colon cancer cells induces apoptosis. Colon cancer cells silence SLC5A8, the gene coding for a Na(+)-coupled pyruvate transporter. Heterologous expression of SLC5A8 in the human colon cancer cell line SW480 leads to inhibition of HDAC activity when cultured in the presence of pyruvate. This process is associated with an increase in intracellular levels of pyruvate, increase in the acetylation status of histone H4, and enhanced cell death. These studies show that cancer cells effectively maintain low levels of pyruvate to prevent inhibition of HDAC1/HDAC3 and thereby to evade cell death.
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PMID:Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3. 1878 2

It has been proposed that cancer prevention results from multiple dietary agents acting together as "action packages." Here we obtain evidence that butyrate, which is generated from dietary fiber, enhances the responsiveness of colon cancer cells to all-trans retinoic acid (ATRA). Evidence was obtained that this interaction depends on histone deactylase one (HDAC1) inhibition by butyrate and retinoic acid receptor alpha (RARalpha) activation by ATRA. The enhancement of RAR beta 2 (RARbeta2) activation was accompanied by a rapid demethylation of the RARbeta2 promoter. This demethylation could be achieved by butyrate alone, and it differed from that triggered by the DNA methyltransferase inhibitor 5-Aza-2' deoxycytidine in that it was 1) sporadic on the RARbeta2 promoter, 2) not genome wide, and 3) independent of extensive DNA replication. An analysis of inter-methylated sites assay indicated that only a few percent of loci analyzed showed reduced methylation. In colon cancer cells that were particularly resistant to RARbeta2 reactivation, the actions of butyrate could be further enhanced by the soy isoflavone genistein, which has also been reported to work through an epigenetic mechanism. These data suggest that dietary compounds that modulate epigenetic programming are likely to function best in the presence of retinoids and other cancer-preventing compounds that are sensitive to a cell's epigenetic state.
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PMID:The short chain fatty acid butyrate induces promoter demethylation and reactivation of RARbeta2 in colon cancer cells. 1879 34

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

Many DNA hypermethylated and epigenetically silenced genes in adult cancers are Polycomb group (PcG) marked in embryonic stem (ES) cells. We show that a large region upstream ( approximately 30 kb) of and extending approximately 60 kb around one such gene, GATA-4, is organized-in Tera-2 undifferentiated embryonic carcinoma (EC) cells-in a topologically complex multi-loop conformation that is formed by multiple internal long-range contact regions near areas enriched for EZH2, other PcG proteins, and the signature PcG histone mark, H3K27me3. Small interfering RNA (siRNA)-mediated depletion of EZH2 in undifferentiated Tera-2 cells leads to a significant reduction in the frequency of long-range associations at the GATA-4 locus, seemingly dependent on affecting the H3K27me3 enrichments around those chromatin regions, accompanied by a modest increase in GATA-4 transcription. The chromatin loops completely dissolve, accompanied by loss of PcG proteins and H3K27me3 marks, when Tera-2 cells receive differentiation signals which induce a approximately 60-fold increase in GATA-4 expression. In colon cancer cells, however, the frequency of the long-range interactions are increased in a setting where GATA-4 has no basal transcription and the loops encompass multiple, abnormally DNA hypermethylated CpG islands, and the methyl-cytosine binding protein MBD2 is localized to these CpG islands, including ones near the gene promoter. Removing DNA methylation through genetic disruption of DNA methyltransferases (DKO cells) leads to loss of MBD2 occupancy and to a decrease in the frequency of long-range contacts, such that these now more resemble those in undifferentiated Tera-2 cells. Our findings reveal unexpected similarities in higher order chromatin conformation between stem/precursor cells and adult cancers. We also provide novel insight that PcG-occupied and H3K27me3-enriched regions can form chromatin loops and physically interact in cis around a single gene in mammalian cells. The loops associate with a poised, low transcription state in EC cells and, with the addition of DNA methylation, completely repressed transcription in adult cancer cells.
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PMID:PcG proteins, DNA methylation, and gene repression by chromatin looping. 2007 2

Chromatin remodeling and activation of transcription are important aspects of gene regulation, but these often go awry in disease progression, including during colon cancer development. We investigated the status of global histone acetylation (by measuring H3, H4 acetylation of lysine residues, which also occur over large regions of chromatin including coding regions and non-promoter sequences) and expression of histone deacetylase 2 (HDAC2) in colorectal cancer (CRC) tissue microarrays using immunohistochemical staining. Specifically, HDAC2 and the acetylation of histones H4K12 and H3K18 were evaluated in 134 colonic adenomas, 55 moderate to well differentiated carcinomas, and 4 poorly differentiated carcinomas compared to matched normal tissue. In addition, the correlation between expression of these epigenetic biomarkers and various clinicopathological factors including, age, location, and stage of the disease were analyzed. HDAC2 nuclear expression was detected at high levels in 81.9%, 62.1%, and 53.1% of CRC, adenomas, and normal tissue, respectively (P = 0.002). The corresponding nuclear global expression levels in moderate to well differentiated tumors for H4K12 and H3K18 acetylation were increased while these levels were decreased in poorly differentiated tumors (P = 0.02). HDAC2 expression was correlated significantly with progression of adenoma to carcinoma (P = 0.002), with a discriminative power of 0.74, when comparing cancer and non-cancer cases. These results suggest HDAC2 expression is significantly associated with CRC progression.
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PMID:Global histone H4 acetylation and HDAC2 expression in colon adenoma and carcinoma. 1905 98

Silencing of multiple cancer-related genes is associated with de novo methylation of linked CpG islands. Additionally, bivalent histone modification profiles characterized by the juxtaposition of active and inactive histone marks have been observed in genes that become hypermethylated in cancer. It is unknown how these ambiguous epigenetic states are maintained and how they interrelate with adjacent genomic regions with different epigenetic landscapes. Here, we present the analysis of a set of neighboring genes, including many frequently silenced in colon cancer cells, in a chromosomal region at 5q35.2 spanning 1.25 Mb. Promoter DNA methylation occurs only at genes maintained at a low transcriptional state and is characterized by the presence of bivalent histone marks, namely trimethylation of lysines 4 and 27 in histone 3. Chemically induced hyperacetylation and DNA demethylation lead to up-regulation of silenced genes in this locus yet do not resolve bivalent domains into a domain-wide active chromatin conformation. In contrast, active genes in the region become down-regulated after drug treatment, accompanied by a partial loss of chromatin domain boundaries and spreading of the inactive histone mark trimethylated lysine 27 in histone 3. Our results demonstrate that bivalent domains mark the promoters of genes that will become DNA methylated in adult tumor cells to enforce transcriptional silence. These bivalent domains not only remain upon drug induced gene reactivation, but also spread over adjacent CpG islands. These results may have important implications in understanding and managing epigenetic therapies of cancer.
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PMID:Bivalent domains enforce transcriptional memory of DNA methylated genes in cancer cells. 1906 Feb

We previously performed a high-throughput screen using real-time noninvasive bioluminescence imaging of p53 transcriptional activity and identified a group of small molecules that trigger p53-like transcriptional responses in p53-deficient tumor cells. Here we further examined the anti-tumor effects of selected compounds in vitro and showed that NSC176327, a derivative of the cytotoxic plant alkaloid ellipticine, exhibited strong anti-neoplastic effect sin wild-type p53, p53-mutant or p53-deficient human colon cancer cells. NSC176327 was more potent at inhibiting tumor cell growth as compared to chemotherapeutic drugs and other ellipticine derivatives and induced cell cycle arrest and apoptosis. Surprisingly, unlike what is observed with the parent compound ellipticine, a DNA damage signaling response was not observed with NSC176327 as evidenced by lack of phosphorylated histone H2AX foci in NSC176327-treated tumor cells. NSC176327 treatment caused a significant increase in p53-activated reporter signal in HCT116, SW620 and HCT116 p53-/- cells and upregulated DR5 and p21 protein expression. NSC176327 treatment also resulted in increased p73 protein expression and knockdown of transactivating isoforms of p73 in HCT116 p53-/- cells showed significant resistance to drug treatment. These results demonstrate an important role of p73 in the anti-tumor effects of NSC176327,and suggest that a close analogue of ellipticine may act by a non-genotoxic mechanism targeting the p53/p73 pathway as compared to the original parent compound that targets the same pathway.
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PMID:Non-genotoxic anti-neoplastic effects of ellipticine derivative NSC176327 in p53-deficient human colon carcinoma cells involve stimulation of p73. 1910 35

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

The Tip60 histone acetyltransferase belongs to a multimolecular complex that contains many chromatin remodeling enzymes including the ATPase p400, a protein involved in nucleosomal incorporation of specific histone variants and that can directly or indirectly repress some Tip60-dependent pathways. Tip60 activity is critical for the cellular response to DNA damage and is affected during cancer progression. Here, we found that the ratio between Tip60 and p400 mRNAs is affected in most colorectal carcinoma. Strikingly, reversing the p400/Tip60 imbalance by Tip60 overexpression or the use of siRNAs resulted in increased apoptosis and decreased proliferation of colon-cancer-derived cells, suggesting that this ratio defect is important for cancer progression. Furthermore, we demonstrate that the p400/Tip60 ratio controls the oncogene-induced DNA damage response, a known anticancer barrier. Finally, we found that it is also critical for the response to 5-fluorouracil, a first-line treatment against colon cancer. Together, our data indicate that the p400/Tip60 ratio is critical for colon cancer cells proliferation and response to therapeutic drugs through the control of stress-response pathways.
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PMID:The p400/Tip60 ratio is critical for colorectal cancer cell proliferation through DNA damage response pathways. 1916 79


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