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Candelaria M de la Cruz-Hernandez E Taja-Chayeb L Perez-Cardenas E Trejo-Becerril C Gonzalez-Fierro A Chavez-Blanco A Soto-Reyes E Dominguez G Trujillo JE Diaz-Chavez J Duenas-Gonzalez A 《PloS one》2012,7(3):e29181
Background
Down regulation of genes coding for nucleoside transporters and drug metabolism responsible for uptake and metabolic activation of the nucleoside gemcitabine is related with acquired tumor resistance against this agent. Hydralazine has been shown to reverse doxorubicin resistance in a model of breast cancer. Here we wanted to investigate whether epigenetic mechanisms are responsible for acquiring resistance to gemcitabine and if hydralazine could restore gemcitabine sensitivity in cervical cancer cells.Methodology/Principal Findings
The cervical cancer cell line CaLo cell line was cultured in the presence of increasing concentrations of gemcitabine. Down-regulation of hENT1 & dCK genes was observed in the resistant cells (CaLoGR) which was not associated with promoter methylation. Treatment with hydralazine reversed gemcitabine resistance and led to hENT1 and dCK gene reactivation in a DNA promoter methylation-independent manner. No changes in HDAC total activity nor in H3 and H4 acetylation at these promoters were observed. ChIP analysis showed H3K9m2 at hENT1 and dCK gene promoters which correlated with hyper-expression of G9A histone methyltransferase at RNA and protein level in the resistant cells. Hydralazine inhibited G9A methyltransferase activity in vitro and depletion of the G9A gene by iRNA restored gemcitabine sensitivity.Conclusions/Significance
Our results demonstrate that acquired gemcitabine resistance is associated with DNA promoter methylation-independent hENT1 and dCK gene down-regulation and hyper-expression of G9A methyltransferase. Hydralazine reverts gemcitabine resistance in cervical cancer cells via inhibition of G9A histone methyltransferase. 相似文献2.
Rodrigo?González-Barrios Ernesto?Soto-Reyes Ricardo?Quiroz-Baez Eunice?Fabián-Morales José?Díaz-Chávez Victor?del Castillo Julia?Mendoza Alejandro?López-Saavedra Clementina?Castro Luis?A?HerreraEmail author 《Cell division》2014,9(1):6
Background
Heterochromatin protein 1 (HP1) is important in the establishment, propagation, and maintenance of constitutive heterochromatin, especially at the pericentromeric region. HP1 might participate in recruiting and directing Mis12 to the centromere during interphase, and HP1 disruption or abrogation might lead to the loss of Mis12 incorporation into the kinetochore. Therefore, the centromere structure and kinetochore relaxation that are promoted in the absence of Mis12 could further induce chromosome instability (CIN) by reducing the capacity of the kinetochore to anchor microtubules. The aim of this study was to determine whether alterations in the localization of HP1 proteins induced by trichostatin A (TSA) modify Mis12 and Centromere Protein A (CENP-A) recruitment to the centromere and whether changes in the expression of HP1 proteins and H3K9 methylation at centromeric chromatin increase CIN in HCT116 and WI-38 cells.Methods
HCT116 and WI-38 cells were cultured and treated with TSA to evaluate CIN after 24 and 48 h of exposure. Immunofluorescence, Western blot, ChIP, and RT-PCR assays were performed in both cell lines to evaluate the localization and abundance of HP1α/β, Mis12, and CENP-A and to evaluate chromatin modifications during interphase and mitosis, as well as after 24 and 48 h of TSA treatment.Results
Our results show that the TSA-induced reduction in heterochromatic histone marks on centromeric chromatin reduced HP1 at the centromere in the non-tumoral WI-38 cells and that this reduction was associated with cell cycle arrest and CIN. However, in HCT116 cells, HP1 proteins, together with MIS12 and CENP-A, relocated to centromeric chromatin in response to TSA treatment, even after H3K9me3 depletion in the centromeric nucleosomes. The enrichment of HP1 and the loss of H3K9me3 were associated with an increase in CIN, suggesting a response mechanism at centromeric and pericentromeric chromatin that augments the presence of HP1 proteins in those regions, possibly ensuring chromosome segregation despite serious CIN. Our results provide new insight into the epigenetic landscape of centromeric chromatin and the role of HP1 proteins in CIN.3.
The centromere is a key region for cell division where the kinetochore assembles, recognizes and attaches to microtubules so that each sister chromatid can segregate to each daughter cell. The centromeric chromatin is a unique rigid chromatin state promoted by the presence of the histone H3 variant CENP-A, in which epigenetic histone modifications of both heterochromatin or euchromatin states and associated protein elements are present. Although DNA sequence is not regarded as important for the establishment of centromere chromatin, it has become clear that this structure is formed as a result of a highly regulated epigenetic event that leads to the recruitment and stability of kinetochore proteins. We describe an integrative model for epigenetic processes that conform regional chromatin interactions indispensable for the recruitment and stability of kinetochore proteins. If alterations of these chromatin regions occur, chromosomal instability is promoted, although segregation may still take place. 相似文献
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Ernesto?Soto-Reyes Luz?María?Del Razo Mahara?Valverde Emilio?RojasEmail author 《Biometals》2005,18(5):493-506
In the last decade arsenic metabolism has become an important matter of discussion. Methylation of inorganic arsenic (iAs)
to monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) is considered to decrease arsenic toxicity. However, in addition to these pentavalent metabolites, the trivalent metabolites
monomethylarsonous (MMAIII) and dimethylarsinous acid (DMAIII) have been identified recently as intermediates in the metabolic pathway of arsenic in cultured human cells. To examine the
role of oxidative damage in the generation of DNA strand breaks by methylated trivalent arsenic metabolites, we treated human
lymphocytes with both metabolites at non-cytotoxic concentrations. We further tested whether these effects are sensitive to
modulation by the antioxidants ascorbate (Vitamin C) and selenomethionine (Se-Met). Both trivalent metabolites produced oxidative
stress related DNA damage, consisting of single strand breaks and alkali-labile sites, with MMAIII being more potent at low concentrations than DMAIII. Neither MMAIII nor DMAIII induced DNA-double strand breaks. The oxidative stress response profiles of the metabolites were parallel as determined by
lipid peroxidation induction. MMAIII induced peroxidation from the lowest concentration tested, while effects of DMAIII were apparent only at concentrations above 10 μM. The antioxidant Se-Met exhibited a more pronounced inhibition of trivalent
arsenic metabolite-induced oxidative-DNA damage than did vitamin C. The present findings suggest that DNA damage by methylated
trivalent metabolites at non-cytotoxic concentrations may be mediated by a mix of reactive oxygen and nitrogen oxidized species. 相似文献
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Carlos-Escalante José Alberto Gómez-Flores-Ramos Liliana Bian Xiaopeng Perdomo-Pantoja Alexander de Andrade Kelvin César Mejía-Pérez Sonia Iliana Cacho-Díaz Bernardo González-Barrios Rodrigo Reynoso-Noverón Nancy Soto-Reyes Ernesto Sánchez-Correa Thalía Estefanía Guerra-Calderas Lissania Yan Chunhua Chen Qingrong Castro-Hernández Clementina Vidal-Millán Silvia Taja-Chayeb Lucía Gutiérrez Olga Álvarez-Gómez Rosa María Gómez-Amador Juan Luis Ostrosky-Wegman Patricia Mohar-Betancourt Alejandro Herrera-Montalvo Luis Alonso Corona Teresa Meerzaman Daoud Wegman-Ostrosky Talia 《Cellular and molecular neurobiology》2021,41(6):1285-1297
Cellular and Molecular Neurobiology - Astrocytoma is the most common type of primary brain tumor. The risk factors for astrocytoma are poorly understood; however, germline genetic variants account... 相似文献
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