V poslední době bylo popsáno několik biologických fenoménů, které se mohou vedle genetických změn významnou měrou též podílet na nádorové transformaci a/nebo progresi nádorů. Mezi tyto jevy řadíme epigenetické změny, RNA interferenci, epiteliálně mezenchymální tranzici a vznik nádorových kmenových buněk. Cílem tohoto článku je podat stručný přehled těchto „negenetických“ procesů ovlivňujících vznik, vzhled, chování, prognózu a léčbu nádorů a poukázat na jejich možné praktické využití především z hlediska diagnostického a terapeutického.

Several biological principles such as epigenetic changes, RNA interference, epithelial-mesenchymal transition, and cancer stem cell formation have been recently connected to the pathobiology of tumors. All these phenomena have, along with genetic changes, a significant impact on the neoplastic transformation and/or tumor progression. Authors report a review of the above mentioned “nongenetic“ processes and their effect on the neoplastic transformation, and the appearance, behavior, prognosis, and therapy of tumors. Future diagnostic and therapeutic perspectives are also discussed.

• MeSH
• biologické jevy MeSH
• diagnostické techniky molekulární metody   trendy   využití   MeSH
• epigeneze genetická genetika   imunologie   účinky léků   MeSH
• epitelové buňky cytologie   patologie   MeSH
• financování organizované MeSH
• lidé MeSH
• metylace DNA účinky léků   MeSH
• nádorová transformace buněk genetika   účinky léků   MeSH
• nádorové kmenové buňky cytologie   patologie   MeSH
• nádory etiologie   genetika   patologie   MeSH
• restrukturace chromatinu genetika   imunologie   účinky léků   MeSH
• RNA interference imunologie   účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Histone variants and their epigenetic modifications determine genome function, particularly transcription. However, whether regulation of gene expression can be influenced by nuclear organization or vice versa is not completely clear. Here, we analyzed the effect of epigenetic changes induced by a histone deacetylase inhibitor (HDACi) on the nuclear radial rearrangement of select genomic regions and chromosomes. The HDACi, sodium butyrate (NaBt), induced differentiation of human adenocarcinoma HT29 cells as well as a genome-wide increase in H3K9 acetylation. Three-dimensional analysis of nuclear radial distributions revealed that this increase in H3K9 acetylation was often associated with a repositioning of select loci and chromosomes toward the nuclear center. On the other hand, many centromeres resided sites more toward the nuclear periphery, similar to sites occupied by chromosome X. In more than two-thirds of events analyzed, central nuclear positioning correlated with a high level of H3K9 acetylation, while more peripheral positioning within interphase nuclei correlated with a lower level of acetylation. This was observed for the gene-rich chromosomes 17 and 19, TP53, and CCND1 genes as well as for gene-poor chromosome 18, APC gene, regions of low transcriptional activity (anti-RIDGEs), and the relatively transcriptionally less active chromosome X. These results are consistent with a role for epigenetic histone modifications in governing the nuclear radial positioning of genomic regions during differentiation.

• MeSH
• acetylace MeSH
• adenokarcinom enzymologie   genetika   MeSH
• buněčná diferenciace MeSH
• buněčné jádro enzymologie   patologie   účinky léků   MeSH
• buňky HT-29 MeSH
• butyráty farmakologie   MeSH
• cyklin D1 genetika   MeSH
• enterocyty účinky léků   enzymologie   patologie   MeSH
• epigeneze genetická účinky léků   MeSH
• financování organizované MeSH
• geny APC MeSH
• histondeacetylasy MeSH
• histony metabolismus   MeSH
• inhibitory enzymů farmakologie   MeSH
• inhibitory histondeacetylas MeSH
• lidé MeSH
• lidské chromozomy, pár 17 metabolismus   MeSH
• lidské chromozomy, pár 18 metabolismus   MeSH
• lidské chromozomy, pár 19 metabolismus   MeSH
• lidské chromozomy metabolismus   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory tračníku enzymologie   genetika   MeSH
• posttranslační úpravy proteinů účinky léků   MeSH
• proliferace buněk MeSH
• promotorové oblasti (genetika) MeSH
• regulace genové exprese u nádorů MeSH
• restrukturace chromatinu účinky léků   MeSH
• Check Tag
• lidé MeSH

Recent studies have shown that histone code dictates the type and structure of chromatin. Bearing in mind the importance of A-type lamins for chromatin arrangement, we studied the effect of trichostatin A (TSA)-induced histone hyperacetylation in lamin A/C-deficient (LMNA-/-) fibroblasts. Lamin A/C deficiency caused condensation of chromosome territories and the nuclear reorganization of centromeric heterochromatin, which was accompanied by the appearance of a chain-like morphology of HP1beta foci. Conversely, histone deacetylase (HDAC) inhibition induced de-condensation of chromosome territories, which compensated the effect of lamin A/C deficiency on chromosome regions. The amount of heterochromatin in the area associated with the nuclear membrane was significantly reduced in LMNA-/- cells when compared with lamin A/C-positive (LMNA+/+) fibroblasts. TSA also decreased the amount of peripheral heterochromatin, similarly as lamin A/C deficiency. In both LMNA+/+ and LMNA-/- cells, physically larger chromosomes were positioned more peripherally as compared with the smaller ones, even after TSA treatment. Our observations indicate that lamin A/C deficiency causes not only reorganization of chromatin and some chromatin-associated domains, but also has an impact on the extent of chromosome condensation. As HDAC inhibition can compensate the lamin A/C-dependent chromatin changes, the interaction between lamins and specifically modified histones may play an important role in higher-order chromatin organization, which influences transcriptional activity.

• MeSH
• acetylace účinky léků   MeSH
• buněčné jádro metabolismus   MeSH
• centromera metabolismus   MeSH
• chromatin metabolismus   účinky léků   MeSH
• fibroblasty metabolismus   MeSH
• financování organizované MeSH
• heterochromatin metabolismus   MeSH
• inhibitory enzymů farmakologie   MeSH
• inhibitory histondeacetylas MeSH
• jaderné proteiny metabolismus   MeSH
• kyseliny hydroxamové farmakologie   MeSH
• lamin typ A genetika   metabolismus   nedostatek   MeSH
• lamin typ B metabolismus   MeSH
• myši MeSH
• restrukturace chromatinu účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH