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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Due to an increase in the understanding of molecular radiobiology, strategies for enhancing tumor radiosensitivity have begun to focus on targeting the molecules and processes that regulate cellular radioresponse. Toward this end, histone acetylation has begun to receive considerable attention as a potential target for radiosensitization. Histone acetylation, which is determined by the competing actions of histone acetylases (HATs) and histone deacetylases (HDACs), plays a role in regulating chromatin structure and gene expression--two parameters that have long been considered determinants of radioresponse. As a means of modifying histone acetylation status, considerable effort has been put into the development of inhibitors of HDAC activity, which is often aberrant in tumor cells. This has led to the generation of a relatively large number of structurally diverse compounds that inhibit HDAC activity and result in histone hyperacetylation, and importantly, are applicable to patient treatment. Whereas a number of these HDAC inhibitors have antitumor activity in preclinical cancer models when delivered as single agents, recent studies have indicated that these compounds also significantly enhance tumor cell radiosensitivity. A structurally diverse set of HDAC inhibitors have been shown to enhance the in vitro radiosensitivity of human tumor cell lines generated from a spectrum of solid tumors. Moreover, HDAC inhibitors increased the radiosensitivity of human tumor xenografts. Although the mechanism responsible for this radiosensitization has not been definitely elucidated, data suggest that inhibiting the repair of radiation-induced DNA damage may be involved. Whereas HDAC inhibitors are currently in clinical trials as single modalities and in combination with chemotherapeutic agents, recent results suggest that these compounds may also enhance the antitumor effectiveness of radiotherapy.
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PMID:Histone deacetylation as a target for radiosensitization. 1678 59

Histone deacetylases (HDACs) are enzymes that regulate the functions of histones as well as nonhistones by catalyzing the removal of acetyl groups from lysine residues. HDACs regulate many biological processes, including the cell division cycle and tumorigenesis. Although recent studies have implicated HDAC8 in tumor cell proliferation, the molecular mechanisms linking HDAC8 to cell growth remain unknown. Here, we report that the human ortholog of the yeast ever-shorter telomeres 1B (EST1B) binds HDAC8. This interaction is regulated by protein kinase A-mediated HDAC8 phosphorylation and protects human EST1B (hEST1B) from ubiquitin-mediated degradation. Phosphorylated HDAC8 preferentially recruits Hsp70 to a complex that inhibits the CHIP (C-terminal heat shock protein interacting protein) E3 ligase-mediated degradation of hEST1B. Importantly, HDAC8 regulation of hEST1B protein stability modulates total telomerase enzymatic activity. Our findings reveal a novel mechanism by which HDAC8 contributes to tumorigenesis by regulating telomerase activity.
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PMID:Histone deacetylase 8 safeguards the human ever-shorter telomeres 1B (hEST1B) protein from ubiquitin-mediated degradation. 1680 64

Histone modifier proteins have come to the forefront in the study of gene regulation. It is now known that histone methyltransferases, acetytransferases, kinases, ubiquitinases, deacetylases and demethylases orchestrate expression of target genes by modifying both histone and non-histone proteins. The nuclear receptor (NR) superfamily govern such diverse biological processes as development, physiology and disease, including human cancer. The involvement of NR in complexes with coactivators and corepressors is necessary for regulation of target genes. This review focuses on the newly recognized interactions between the NR and histone modifying enzymes. In addition to regulating histones, the histone modifying proteins directly modify and thereby regulate NR activity. In the same manner that signaling platforms exist within the histone tails that are post-translationally processed by histone modifying proteins, cascades of post-translational modification have been identified within the NR that coordinate their activity. This review focuses on the regulation of the NR estrogen receptor (ERalpha), androgen receptor (AR) and peroxisome proliferator activated receptor-gamma (PPARgamma), given their role in tumor onset and progression.
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PMID:Epigenetic regulation of nuclear steroid receptors. 1684 98

Histone acetyltransferases (HATs) regulate transcription, chromatin structure and DNA repair. Here, we utilized a novel HAT inhibitor, anacardic acid, to examine the role of HATs in the DNA damage response. Anacardic acid inhibits the Tip60 HAT in vitro, and blocks the Tip60-dependent activation of the ATM and DNA-PKcs protein kinases by DNA damage in vivo. Further, anacardic acid sensitizes human tumor cells to the cytotoxic effects of ionizing radiation. These results demonstrate a central role for HATs such as Tip60 in regulating the DNA damage response. HAT inhibitors provide a novel therapeutic approach for increasing the sensitivity of tumors to radiation therapy.
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PMID:Inhibition of histone acetyltransferase activity by anacardic acid sensitizes tumor cells to ionizing radiation. 1684 18

Histone deacetylases (HDACs) catalyze the removal of acetyl groups from core histones. Because of their capacity to induce local condensation of chromatin, HDACs are generally considered repressors of transcription. In this report, we analyzed the role of the class I histone deacetylase HDAC1 as a transcriptional regulator by comparing the expression profiles of wild-type and HDAC1-deficient embryonic stem cells. A specific subset of mouse genes (7%) was deregulated in the absence of HDAC1. We identified several putative tumor suppressors (JunB, Prss11, and Plagl1) and imprinted genes (Igf2, H19, and p57) as novel HDAC1 targets. The majority of HDAC1 target genes showed reduced expression accompanied by recruitment of HDAC1 and local reduction in histone acetylation at regulatory regions. At some target genes, the related deacetylase HDAC2 partially masks the loss of HDAC1. A second group of genes was found to be downregulated in HDAC1-deficient cells, predominantly by additional recruitment of HDAC2 in the absence of HDAC1. Finally, a small set of genes (Gja1, Irf1, and Gbp2) was found to require HDAC activity and recruitment of HDAC1 for their transcriptional activation. Our study reveals a regulatory cross talk between HDAC1 and HDAC2 and a novel function for HDAC1 as a transcriptional coactivator.
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PMID:Negative and positive regulation of gene expression by mouse histone deacetylase 1. 1694 Jan 78

Histone deacetylases (HDAC) have been identified as therapeutic targets due to their regulatory function in DNA structure and organization. LBH589 is a novel inhibitor of class I and II HDACs. We studied the effect of LBH589 and ionizing radiation (IR) on DNA repair in two human non-small cell lung cancer (NSCLC) cell lines (H23 and H460). gamma-H2AX foci present at DNA double-strand breaks (DSBs) were detected in the nuclei following 3 Gy irradiation for up to 6 hours. LBH589 administered before irradiation increased the duration of gamma-H2AX foci beyond 24 hours. Furthermore, radiation alone induced translocation of HDAC4 to the nucleus. In contrast, treatment with LBH589 followed by irradiation resulted in HDAC4 confinement to the cytoplasm, indicating that HDAC inhibition affects the nuclear localization of HDAC4. The findings that LBH589 confines HDAC4 to the cytoplasm and increases the duration of gamma-H2AX foci in irradiated cell lines suggest that HDAC4 participates in DNA damage signaling following IR. Annexin-propidium iodide flow cytometry assays, cell morphology studies, and cleaved caspase-3 Western blot analysis revealed a synergistic effect of LBH589 with IR in inducing apoptosis. Clonogenic survival showed a greater than additive effect when LBH589 was administered before irradiation compared with irradiation alone. In vivo tumor volume studies showed a growth delay of 20 days with combined treatment compared with 4 and 2 days for radiation or LBH589 alone. This study identifies HDAC4 as a biomarker of LBH589 activity and recognizes the ability of LBH589 to sensitize human NSCLC to radiation-induced DNA DSBs.
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PMID:Histone deacetylase (HDAC) inhibitor LBH589 increases duration of gamma-H2AX foci and confines HDAC4 to the cytoplasm in irradiated non-small cell lung cancer. 1714 76

Histone deacetylases (HDACs) play a critical role in gene transcription and are implicated in cancer therapy and other diseases. Inhibitors of HDACs induce cell differentiation and suppress cell proliferation in the tumor cells. Although many such inhibitors have been designed and synthesized, but selective inhibitors for HDAC isoforms are lacking. Various hydroxamic acid analogues have been reported as HDAC inhibitors. Here, we report a three-dimensional quantitative structure-activity relationship (3D-QSAR) study performed using genetic function approximation (GFA) for this class of molecules. QSAR models were generated using a training set of 39 molecules and the predictive ability of final model was assessed using a test set of 17 molecules. The internal consistency of the final QSAR model was 0.712 and showed good external predictivity of 0.585. The results of the present QSAR study indicated that molecular shape analysis (MSA). thermodynamic and structural descriptors are important for inhibition of HDACs.
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PMID:3D-QSAR of histone deacetylase inhibitors as anticancer agents by genetic function approximation. 1728

The endocrine signaling governing nuclear receptor (NR) function has been known for several decades to play a crucial role in the onset and progression of several tumor types. Notably among these are the estrogen receptor (ER) in breast cancer and androgen receptor (AR) in prostate cancer. Other nuclear receptors may be involved in cancer progression including the peroxisome-proliferator activating receptor gamma (PPARgamma), which has been implicated in breast, thyroid, and colon cancers. These NR are phylogenetically conserved modular transcriptional regulators, which like histones, undergo post-translational modification by acetylation, phosphorylation and ubiquitination. Importantly, the transcriptional activity of the receptors is governed by the coactivator p300, the activity of which is thought to be rate-limiting in the activity of these receptors. Histone acetyltransferases (HATs) and histone deacetylases (HDACs), modify histones by adding or removing an acetyl group from the epsilon amino group of lysines within an evolutionarily conserved lysine motif. Histone acetylation results in changes in chromatin structure in response to specific signals. These enzymes can also directly catalyze the NRs themselves, thus modifying signals at the receptor level. The post-translational modification of NR which is regulated by hormones, alters the NR function toward a growth promoting receptor. The deacetylation of NR is mediated by TSA-sensitive and NAD-dependent deacetylases. The regulation of NR by NAD-dependent enzymes provides a direct link between intracellular metabolism and hormone signaling.
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PMID:The functional significance of nuclear receptor acetylation. 1729 55

Histone acetylation and histone deacetylation play key roles in the epigenetic regulation. Thus, inhibition of deacetylation controlled by histone deacetylases may result in chromatin remodeling, upregulation of key tumor repressor genes, differentiation or apoptosis. Therefore many naturally occurring and synthetic histone deacetylase inhibitors have been shown to display potent anticancer activities in preclinical studies. The exact mechanism by which histone deacetylases exert their effect, however, is still obscure; in any case it is more complicated than originally understood. Although several representatives of this novel class of therapeutic agents are currently at early stages of clinical development, rational design leading to highly selective histone deacetylase inhibitors against histone deacetylase isoforms will not only probably offer more potent anticancer drugs, but also critical insights into their mechanism of action.
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PMID:Histone deacetylase inhibitors for epigenetic therapy of cancer. 1735 88

Epigenetics is defined as mitotically and meiotically heritable changes in gene expression that do not involve a change in the DNA sequence. Two major areas of epigenetics-DNA methylation and histone modifications-are known to have profound effects on controlling gene expression. DNA methylation is involved in normal cellular control of expression, and aberrant hypermethylation can lead to silencing of tumor-suppressor genes in carcinogenesis. Histone modifications control the accessibility of the chromatin and transcriptional activities inside a cell. MicroRNAs (miRNAs) are small RNA molecules, approximately 22 nucleotides long that can negatively control their target gene expression posttranscriptionally. There are currently more than 460 human miRNAs known, and the total number is predicted to be much larger. Recently, the expression of miRNAs has been definitively linked to cancer development, and miRNA profiles can be used to classify human cancers. miRNAs are encoded in our genome and are generally transcribed by RNA polymerase II. Despite the growing evidence for their importance in normal physiology, little is known about the regulation of miRNA expression. In this review, we will examine the relationship between miRNAs and epigenetics. We examine the effects of miRNAs on epigenetic machinery, and the control of miRNA expression by epigenetic mechanisms. Epigenetics is defined as heritable changes in gene expression that do not involve a change in DNA sequence.
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PMID:Epigenetics and microRNAs. 1741 52


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