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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In recent years the study of chemical modifications to chromatin and their effects on cellular processes has become increasingly important in the field of cancer research. Disruptions to the normal epigenetic pattern of the cell can serve as biomarkers and are important determinants of cancer progression. Accordingly, drugs that inhibit the enzymes responsible for modulating these epigenetic markers, in particular histone deacetylases, are the focus of intense research and development. In this chapter we provide an overview of class I and II histone deacetylases as well as a guide to the diverse types of histone deacetylase inhibitors and their activities in the context of APL. We also discuss the rationale for the use of histone deacetylase inhibitors in combination therapy for the treatment of cancer and the current status of clinical trials.
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PMID:Histone deacetylase inhibitors in APL and beyond. 1721 44

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

Alterations in epigenetic gene regulation are associated with human disease. Here, we discuss connections between DNA methylation and histone methylation, providing examples in which defects in these processes are linked with disease. Mutations in genes encoding DNA methyltransferases and proteins that bind methylated cytosine residues cause changes in gene expression and alterations in the patterns of DNA methylation. These changes are associated with cancer and congenital diseases due to defects in imprinting. Gene expression is also controlled through histone methylation. Altered levels of methyltransferases that modify lysine 27 of histone H3 (K27H3) and lysine 9 of histone H3 (K9H3) correlate with changes in Rb signaling and disruption of the cell cycle in cancer cells. The K27H3 mark recruits a Polycomb complex involved in regulating stem cell pluripotency, silencing of developmentally regulated genes, and controlling cancer progression. The K9H3 methyl mark recruits HP1, a structural protein that plays a role in heterochromatin formation, gene silencing, and viral latency. Cells exhibiting altered levels of HP1 are predicted to show a loss of silencing at genes regulating cancer progression. Gene silencing through K27H3 and K9H3 can involve histone deacetylation and DNA methylation, suggesting cross talk between epigenetic silencing systems through direct interactions among the various players. The reversible nature of these epigenetic modifications offers therapeutic possibilities for a wide spectrum of disease.
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PMID:Connections between epigenetic gene silencing and human disease. 1730 46

Tumor cell dedifferentiation-such as the loss of cell-to-cell adhesion in epithelial tumors-is associated with tumor progression. To better understand the mechanisms that maintain carcinoma cells in a differentiated state, we have dissected in vitro differentiation pathways in the mucus-secretor HT-29 M6 colon cancer cell line, which spontaneously differentiates in postconfluent cultures. By lowering the extracellular calcium concentration to levels that prevent intercellular adhesion and epithelial polarization, our results reveal that differentiation is calcium-dependent and involves: (i) a process of cell cycle exit to G(0) and (ii) the induction of a transcriptional program of differentiation gene expression (i.e., mucins MUC1 and MUC5AC, and the apical membrane peptidase DPPIV). In calcium-deprived, non-differentiated postconfluent cultures, differentiation gene promoters are repressed by a trichostatin A (TSA)-sensitive mechanism, indicating that loss of gene expression by dedifferentiation is driven by histone deacetylases (HDAC). Since TSA treatment or extracellular calcium restoration allow gene promoter activation to similar levels, we suggest that induction of differentiation is one mechanism of HDAC inhibitor antitumor action. Moreover, transcriptional de-repression can also be induced in non-differentiating culture conditions by overexpressing the cyclin-dependent kinase inhibitor p27(KIP1), which is normally induced during spontaneous differentiation. Since p27(KIP1) downregulation in colon cancer is associated with poor prognosis independently of tumor cell division rates, we propose that p27 (KIP1) may prevent tumor progression by, at least in part, enhancing the expression of some differentiation genes. Therefore, the HT-29 M6 model allows the identification of some basic mechanisms of cancer cell differentiation control, so far revealing HDAC and p27(KIP1) as key regulatory factors of differentiation gene expression.
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PMID:In vitro differentiation of HT-29 M6 mucus-secreting colon cancer cells involves a trychostatin A and p27(KIP1)-inducible transcriptional program of gene expression. 1731 Dec 91

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase polycomb group (PcG) protein, which has been implicated in the process of cellular differentiation and cancer progression for both breast and prostate cancer. Although transcriptional repression by histone modification appears to contribute to the process of cellular differentiation, it is unclear what mediates the specificity of PcG proteins. Since EZH2 requires a binding partner for its histone methyltransferase activity, we surmised that evaluating interacting proteins might shed light on how the activity of EZH2 is regulated. Here we describe the identification of a novel binding partner of EZH2, the repressor of estrogen receptor activity (REA). REA functions as a transcriptional corepressor of the estrogen receptor and can potentiate the effect of anti-estrogens. REA expression levels have also previously been associated with the degree of differentiation of human breast cancers. We show here that EZH2 can also mediate the repression of estrogen-dependent transcription, and that moreover, the ability of both REA and EZH2 to repress estrogen-dependent transcription are mutually dependent. These data suggest that EZH2 may be recruited to specific target genes by its interaction with the estrogen receptor corepressor REA. The identification of a novel interaction between EZH2 and REA, two transcription factors that have been linked to breast cancer carcinogenesis, may lead to further insights into the process of deregulated gene expression in breast cancer.
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PMID:EZH2 regulates the transcription of estrogen-responsive genes through association with REA, an estrogen receptor corepressor. 1745 41

Prostate cancer is the most common type of cancer other than skin cancer and the second leading cause of cancer death in men in the United States. Its exact causes are unknown. Several risk factors have been associated with prostate cancer including age, race, family history and diet. Epigenetic mechanisms including DNA methylation and histone modifications are important means of gene regulation and play essential roles in diverse biological and disease processes. Recently, frequent epigenetic aberrations such as DNA hypo- and hypermethylation and altered histone acetylation and methylation have been observed in prostate cancer affecting the expression and function of a large array of genes, leading to tumorigenesis, tumor progression and metastasis. In this chapter, we examined the current literature regarding epigenetic changes in prostate cancer and discuss the clinical potential of cancer epigenetics for the diagnosis and treatment of this disease.
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PMID:Epigenetics of prostate cancer. 1748 7

Tumor initiation and progression provide a multitude of occasions for the generation of DNA damage and the consequent activation of the DNA damage response (DDR) pathway. DDR signaling involves the engagement of key factors such as ATM, CHK2, 53BP1 and the phosphorylation of histone H2AX (gamma-H2AX). The systematic study of DDR in human tumors and normal tissues by high-throughput tissue microarrays revealed that ATM and gamma-H2AX were engaged in cancer but the extent of their activation was strongly affected by the organ and cell type involved, whereas 53BP1 loss was the most consistent feature among the tumor studied. Unexpectedly, we also observed activated DDR markers in morphologically normal tissues, also in association with inflammation. Analysis of the dynamic engagement of DDR along the different stages of lung tumorigenesis showed that 53BP1 loss occurs early at the transition from normal to dysplastic change whereas the activated forms of ATM and CHK2, but not gamma-H2AX, initially accumulate in pre-invasive lesions and are then lost during tumor progression. In individual lung tumors, the activation of ATM, CHK2 and the presence of 53BP1 were consistently correlated, whereas gamma-H2AX did not correlate with activated ATM. Finally, the study of associations between critical clinicopathological parameters and activated DDR factors highlighted a statistically meaningful correlation between reduced local tumor extension and the phosphorylation of ATM, CHK2 and the presence of 53BP1, whereas no significant correlations with parameters such as survival or relapse of early-stage lung carcinomas were found.
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PMID:Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression. 1752 62

Histone modifications, such as acetylation and methylation, are important epigenetic marks that regulate diverse biological processes that use chromatin as the template, including transcription. Dysregulation of histone acetylation and methylation leads to the silencing of tumor suppressor genes and contributes to cancer progression. Inhibitors of enzymes that catalyze the addition and removal of these epigenetic marks thus have therapeutic potential for treating cancer. Lysine-specific demethylase 1 (LSD1) is the first discovered histone lysine demethylase and, with the help of its cofactor CoREST, specifically demethylates mono- and dimethylated histone H3 lysine 4 (H3-K4), thus repressing transcription. Because LSD1 belongs to the family of flavin adenine dinucleotide (FAD)-dependent amine oxidases, certain inhibitors of monoamine oxidases (MAOs), including the clinically used antidepressant trans-2-phenylcyclopropylamine (PCPA; tranylcypromine; Parnate), are also capable of inhibiting LSD1. In this study, we have further measured the kinetic parameters of the inhibition of LSD1 by PCPA and determined the crystal structure of LSD1-CoREST in the presence of PCPA. Our structural and mass spectrometry analyses are consistent with PCPA forming a covalent adduct with FAD in LSD1 that is distinct from the FAD-PCPA adduct of MAO B. The structure also reveals that the phenyl ring of the FAD-PCPA adduct in LSD1 does not form extensive interactions with active-site residues. This study thus provides the basis for designing more potent inhibitors of LSD1 that contain substitutions on the phenyl ring of PCPA to fully engage neighboring residues.
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PMID:Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine. 1756 9

T-box transcription factors play a crucial role in development where they are implicated in patterning and cell fate decisions. Tbx2 and Tbx3 have also been implicated in several cancers including melanoma, and can act as antisenescence factors through their ability to repress p19(ARF) and p21(CIP1) expression. Although several target genes for T-box factors have been identified, it is unknown whether this family of proteins can bind chromatin, a property that would facilitate the epigenetic reprogramming that occurs in both development and cancer progression. Here, we show that Tbx2 has the potential to recognize mitotic chromatin in a DNA-dependent fashion, can interact specifically with the histone H3 N-terminal tail, a property shared with Tbx4, Tbx5 and Tbx6, and can also recognize nucleosomal DNA, with binding to nucleosomes being antagonized by the presence of the histone tails. Strikingly, in vivo Tbx2 co-localization with pericentric heterochromatin appears to be regulated and ectopic expression of Tbx2 leads to severe mitotic defects. Taken together our results suggest that Tbx2, and most likely other members of the T-box family, are able to target chromatin and may indicate a role for the T-box factors in epigenetic reprogramming events.
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PMID:T-box factors: targeting to chromatin and interaction with the histone H3 N-terminal tail. 1763 Sep 61

Cellular senescence is an irreversible proliferation arrest of primary cells and an important tumor suppression process. Senescence is often characterized by domains of facultative heterochromatin, called senescence-associated heterochromatin foci (SAHF), which repress expression of proliferation-promoting genes. Formation of SAHF is driven by a complex of histone chaperones, HIRA and ASF1a, and depends upon prior localization of HIRA to PML nuclear bodies. However, how the SAHF assembly pathway is activated in senescent cells is not known. Here we show that expression of the canonical Wnt2 ligand and downstream canonical Wnt signals are repressed in senescent human cells. Repression of Wnt2 occurs early in senescence and independently of the pRB and p53 tumor suppressor proteins and drives relocalization of HIRA to PML bodies, formation of SAHF and senescence, likely through GSK3beta-mediated phosphorylation of HIRA. These results have major implications for our understanding of both Wnt signaling and senescence in tissue homeostasis and cancer progression.
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PMID:Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells. 1764 69


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