共查询到20条相似文献,搜索用时 15 毫秒
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Hong-Bin Wang Hong Wei Jin-Song Wang Lin Li An-Yue Chen Zhi-Gao Li 《生物化学与生物物理学报:疾病的分子基础》2019,1865(3):708-723
Breast cancer (BC)-related mortality is associated with the potential metastatic properties of the primary breast tumors. The following study was conducted with the main focus on the effect of LINC00518 on the growth and metastasis of BC epithelial cells via the Wnt signaling pathway through regulation of the methylation of CDX2 gene. Initially, differentially expressed long intergenic non-protein coding RNAs (lincRNAs) related to BC were screened out in the Cancer Genome Atlas (TCGA) database, after which we detected the LINC00518 expression and localization in BC tissues and cells. Then the CDX2 positive expression and methylation level were identified. The targeting relationship of LINC00518 and CDX2, and binding methyltransferase in the promoter region were examined. BC epithelial cell proliferation, colony formation ability, invasion, migration and apoptosis were further evaluated. The lincRNA expression data related to BC downloaded from the TCGA database revealed that there was a high expression of LINC00518 in BC, and a negative correlation between LINC00518 and CDX2. In addition, LINC00518 promotes CDX2 methylation by recruiting DNA methyltransferase through activating the Wnt signaling pathway. The down-regulation of LINC00518 inhibited proliferation, invasion, migration, and EMT of BC epithelial cells while enhancing apoptosis. The inhibitory effects of LINC00518 down-regulation was reversed by CDX2 down-regulation. In conclusion, our findings revealed that down-regulation of LINC00518 might have the ability to suppress BC progression by up-regulating CDX2 expression through the reduction of methylation and blockade of the Wnt signaling pathway, resulting in the inhibition of proliferation and promotion of apoptosis of BC epithelial cells. 相似文献
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We have previously shown that Ras mediates NO-induced BNIP3 expression via the MEK-E RK-HIF-1 pathway i n mouse macrophages, and that NO-induced death results at least in part from the induction of
BNIP3. In the present study, we describe another aspect of Ras regulation of BNIP3 expression in pancreatic cancer cells.
Human BNIP3 promoter-driven luciferase activity was efficiently induced by activated Ras in AsPC-1, Miapaca-2, PK-1 and PANC-1
cells. However, expression of endogenous BNIP3 was not induced, and BNIP3 up-regulation by hypoxia was also inhibited. Treatment
of the cells with the DNMT inhibitor, 5-aza-2-deoxycytidine, restored BNIP3 induction, indicating that DNA methylation of
the BNIP3 promoter was responsible for the inhibition of BNIP3 induction. Furthermore, inhibition of the MEK pathway with
U0126 reduced DNMT1 expression, but not that of DNMT3a and 3b, and restored the hypoxia-inducibility of BNIP3, suggesting
that the DNA methylation of the BNIP3 promoter was mediated by DNMT1 via the MEK pathway. 相似文献
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Yuan Sun Peyman Sahbaie DeYong Liang Wenwu Li Xiaoyou Shi Paige Kingery J. David Clark 《PloS one》2015,10(11)
DNA methylation is a key epigenetic mechanism controlling DNA accessibility and gene expression. Blockade of DNA methylation can significantly affect pain behaviors implicated in neuropathic and inflammatory pain. However, the role of DNA methylation with regard to postoperative pain has not yet been explored. In this study we sought to investigate the role of DNA methylation in modulating incisional pain and identify possible targets under DNA methylation and contributing to incisional pain. DNA methyltranferase (DNMT) inhibitor 5-Aza-2′-deoxycytidine significantly reduced incision-induced mechanical allodynia and thermal sensitivity. Aza-2′-deoxycytidine also reduced hindpaw swelling after incision, suggesting an anti-inflammatory effect. Global DNA methylation and DNMT3b expression were increased in skin after incision, but none of DNMT1, DNMT3a or DNMT3b was altered in spinal cord or DRG. The expression of proopiomelanocortin Pomc encoding β-endorphin and Oprm1 encoding the mu-opioid receptor were upregulated peripherally after incision; moreover, Oprm1 expression was further increased under DNMT inhibitor treatment. Finally, local peripheral injection of the opioid receptor antagonist naloxone significantly exacerbated incision-induced mechanical hypersensitivity. These results suggest that DNA methylation is functionally relevant to incisional nociceptive sensitization, and that mu-opioid receptor signaling might be one methylation regulated pathway controlling sensitization after incision. 相似文献
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V.K. Chaithanya Ponnaluri Pierre-Olivier Estève Cristian I. Ruse Sriharsa Pradhan 《Journal of molecular biology》2018,430(14):2051-2065
DNA (cytosine-5) methyltransferase 1 (DNMT1) is essential for mammalian development and maintenance of DNA methylation following DNA replication in cells. The DNA methylation process generates S-adenosyl-l-homocysteine, a strong inhibitor of DNMT1. Here we report that S-adenosylhomocysteine hydrolase (SAHH/AHCY), the only mammalian enzyme capable of hydrolyzing S-adenosyl-l-homocysteine binds to DNMT1 during DNA replication. SAHH enhances DNMT1 activity in vitro, and its overexpression in mammalian cells led to hypermethylation of the genome, whereas its inhibition by adenosine periodate or siRNA-mediated knockdown resulted in hypomethylation of the genome. Hypermethylation was consistent in both gene bodies and repetitive DNA elements leading to aberrant gene regulation. Cells overexpressing SAHH specifically up-regulated metabolic pathway genes and down-regulated PPAR and MAPK signaling pathways genes. Therefore, we suggest that alteration of SAHH level affects global DNA methylation levels and gene expression. 相似文献
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Inactive DNA methyltransferase (DNMT) 3B splice isoforms are associated with changes in DNA methylation, yet the mechanisms by which they act remain largely unknown. Using biochemical and cell culture assays, we show here that the inactive DNMT3B3 and DNMT3B4 isoforms bind to and regulate the activity of catalytically competent DNMT3A or DNMT3B molecules. DNMT3B3 modestly stimulated the de novo methylation activity of DNMT3A and also counteracted the stimulatory effects of DNMT3L, therefore leading to subtle and contrasting effects on activity. DNMT3B4, by contrast, significantly inhibited de novo DNA methylation by active DNMT3 molecules, most likely due to its ability to reduce the DNA binding affinity of co-complexes, thereby sequestering them away from their substrate. Immunocytochemistry experiments revealed that in addition to their effects on the intrinsic catalytic function of active DNMT3 enzymes, DNMT3B3 and DNMT34 drive distinct types of chromatin compaction and patterns of histone 3 lysine 9 tri-methylation (H3K9me3) deposition. Our findings suggest that regulation of active DNMT3 members through the formation of co-complexes with inactive DNMT3 variants is a general mechanism by which DNMT3 variants function. This may account for some of the changes in DNA methylation patterns observed during development and disease. 相似文献
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Recent studies have suggested that Hippo signaling is not only involved in controlling organ size in Drosophila but can also regulate cell proliferation, tissue homeostasis, differentiation, apoptosis and regeneration. Any dysregulation of Hippo signaling, especially the hyper activation of its downstream effectors YAP/TAZ, can lead to uncontrolled cell proliferation and malignant transformation. In majority of cancers, expression of YAP/TAZ is extremely high and this increased expression of YAP/TAZ has been shown to be an independent predictor of prognosis and indicator of increased cell proliferation, metastasis and poor survival. In this review, we have summarized the most recent findings about the cross talk of Hippo signaling pathway with other signaling pathways and its regulation by different miRNAs in various cancer types. Recent evidence has suggested that Hippo pathway is also involved in mediating the resistance of different cancer cells to chemotherapeutic drugs and in a few cancer types, this is brought about by regulating miRNAs. Therefore, the delineation of the underlying mechanisms regulating the chemotherapeutic resistance might help in developing better treatment options. This review has attempted to provide an overview of different drugs/options which can be utilized to target oncogenic YAP/TAZ proteins for therapeutic interventions. 相似文献
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Ting Liu Ping Ye Yuanyuan Ye Baosan Han 《International journal of biological sciences》2021,17(11):2970
Patients suffering from breast cancer (BC) still have a poor response to treatments, even though early detection and improved therapy have contributed to a reduced mortality. Recent studies have been inspired on the association between microRNAs (miRs) and therapies of BC. The current study set out to investigate the role of miR-216b in BC, and further analyze the underlining mechanism. Firstly, hexokinase 2 (HK2) and miR-216b were characterized in BC tissues and cells by RT-qPCR and Western blot assay. In addition, the interaction between HK2 and miR-216b was analyzed using dual luciferase reporter assay. BC cells were further transfected with a series of miR-216b mimic or inhibitor, or siRNA targeting HK2, so as to analyze the regulatory mechanism of miR-216b, HK2 and mammalian target of rapamycin (mTOR) signaling pathway, and to further explore their regulation in BC cellular behaviors. The results demonstrated that HK2 was highly expressed and miR-216b was poorly expressed in BC cells and tissues. HK2 was also verified as a target of miR-216b with online databases and dual luciferase reporter assay. Functionally, miR-216b was found to be closely associated with BC progression via inactivating mTOR signaling pathway by targeting HK2. Moreover, cell viability, migration and invasion were reduced as a result of miR-216b upregulation or HK2 silencing, while autophagy, cell cycle arrest and apoptosis were induced. Taken together, our findings indicated that miR-216b down-regulates HK2 to inactivate the mTOR signaling pathway, thus inhibiting the progression of BC. Hence, this study highlighted a novel target for BC treatment. 相似文献
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Bethany L. Wienholz Michael S. Kareta Amir H. Moarefi Catherine A. Gordon Paul A. Ginno Frédéric Chédin 《PLoS genetics》2010,6(9)
The DNTM3A and DNMT3B de novo DNA methyltransferases (DNMTs) are responsible for setting genomic DNA methylation patterns, a key layer of epigenetic information. Here, using an in vivo episomal methylation assay and extensive bisulfite methylation sequencing, we show that human DNMT3A and DNMT3B possess significant and distinct flanking sequence preferences for target CpG sites. Selection for high or low efficiency sites is mediated by the base composition at the −2 and +2 positions flanking the CpG site for DNMT3A, and at the −1 and +1 positions for DNMT3B. This intrinsic preference reproducibly leads to the formation of specific de novo methylation patterns characterized by up to 34-fold variations in the efficiency of DNA methylation at individual sites. Furthermore, analysis of the distribution of signature methylation hotspot and coldspot motifs suggests that DNMT flanking sequence preference has contributed to shaping the composition of CpG islands in the human genome. Our results also show that the DNMT3L stimulatory factor modulates the formation of de novo methylation patterns in two ways. First, DNMT3L selectively focuses the DNA methylation machinery on properly chromatinized DNA templates. Second, DNMT3L attenuates the impact of the intrinsic DNMT flanking sequence preference by providing a much greater boost to the methylation of poorly methylated sites, thus promoting the formation of broader and more uniform methylation patterns. This study offers insights into the manner by which DNA methylation patterns are deposited and reveals a new level of interplay between members of the de novo DNMT family. 相似文献
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Breast cancer ranks as the major reason for mortality in women populations, accounting for 23% of all cancer deaths. One in every three Asian women encounters the risk of this cancer in their lifetime. Long intergenic non-coding RNAs (lincRNAs) have emerged as tumor promoters and suppressors. The molecular mechanism of breast cancer remains elusive. Therefore, the current study aimed to explore the role lincRNA LINC00922 plays in the development of breast cancer. Breast cancer tissues and adjacent tissues were obtained from 109 patients with breast cancer. The RNA extraction and quantification and immunohistochemical staining characterized the high expression of LINC00922 and low expression of NKD2 in breast cancer tissues in comparison to its adjacent counterparts. Furthermore, the ectopic expression and knockdown experiments were conducted to figure out the in vivo and in vitro effects of LINC00922 on breast cancer progression. The ectopically expressed LINC00922 activated the Wnt signaling pathway, promoted epithelial-mesenchymal transition, cell proliferative, invasive and migratory capacities, tumor growth and metastasis. Additionally, the RIP and ChIP assay identified that LINC00922 recruited DNMT1, DNMT3A and DNMT3B proteins in the promoter region of NKD2 to promote NKD2 promoter methylation, thus reducing the NKD2 expression. Moreover, the Wnt signaling pathway was activated subsequent to NKD2 silencing, which was reversed by LINC00922 silencing. Lastly, the anti-oncogenic effects of LINC00922 inhibition was antagonized after NKD2 knocked down. The current study provides evidence that LINC00922 acts as a tumor promoter by promoting NKD2 methylation. Hopefully, it provides a novel potential gene target for the treatment of breast cancer. 相似文献
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Defeng Qi Jinhui Li Biao Que Jialin Su Mengxi Li Chaofeng Zhang Mei Yang Guoren Zhou Weidong Ji 《Cancer cell international》2015,16(1):81