Methyltransferase expression and tumor suppressor gene methylation in sporadic and familial colorectal cancer

Joensuu, Emmi I.; Nieminen, Taina T.; Lotsari, Johanna E.; Pavicic, Walter Hernán; Abdel‐Rahman, Wael M.; Peltomäki, Païvi

doi:10.1002/gcc.22289

Cited by 14 publications

(7 citation statements)

References 63 publications

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“…DNMT3b functions as a de novo methyltransferase that establishes new DNA methylation patterns, 43 over-expression and hyperactivation of DNMT3b, which can result in hypermethylation of promoter CpG islands and gene silence. 44 In the present study, we disclosed that HPostC can induce DNA hypomethylation of the miR-30a promoter and…”

Section: Conflict Of Interestsmentioning

confidence: 50%

DNA Hypomethylation of miR-30a Mediated the Protection of Hypoxia Postconditioning Against Aged Cardiomyocytes Hypoxia/Reoxygenation Injury Through Inhibiting Autophagy

Wang

Hao

Zhang

et al. 2020

Circ J

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Background: Ischemic postconditioning (IPostC) is an endogenous protective mechanism to reduce ischemia-reperfusion (I/R) injury. However, whether IPostC protects aged cardiomyocytes against I/R injury is not fully understood. Considering the protective function of microRNA 30a (miR-30a) against ischemia-induced injury in H9C2 cells, its role in the protective effects of IPostC on I/R injury of aged cardiomyocytes was investigated further. Methods and Results: To mimic I/R and IPostC in vitro, the aged cardiomyocyte model for hypoxia postconditioning (HPostC) treatment was established by 9 days of incubation with 8 mg/mL D-galactose and then followed by exposure to hypoxic environment. HPostC significantly alleviated hypoxia/reoxygenation (H/R) injury and reduced autophagy of aged cardiomyocytes, as evidenced by decreased LC3B-II expression and increased p62 by Western blot. Quantified by quantitative real-time polymerase chain reaction (qRT-PCR), miR-30a was increased in aged cardiomyocytes treated with HPostC compared with I/R injury group. Overexpression of miR-30a by LV3-rno-miR-30a mimic promoted cardioprotective effect of HPostC in aged cardiomyocytes by suppressing BECN1mediated autophagy, all of which was abrogated by knockdown of miR-30a expression. Epigenetic analyses demonstrated that HPostC reduced DNA methyltransferase 3b-mediated DNA hypomethylation levels at miR-30a promoter, leading to upregulation of miR-30a. Conclusions: HPostC protected aged cardiomyocytes survival against H/R injury via DNMT3b-dependent activation of miR-30a. miR-30a could be a potential therapeutic target for ischemic myocardial infarction.

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Section: Conflict Of Interestsmentioning

confidence: 50%

DNA Hypomethylation of miR-30a Mediated the Protection of Hypoxia Postconditioning Against Aged Cardiomyocytes Hypoxia/Reoxygenation Injury Through Inhibiting Autophagy

Wang

Hao

Zhang

et al. 2020

Circ J

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“…This last result, which held multiple test correction, was further confirmed in the replication sample. These results are consistent with previous data demonstrating that changes in the methylation levels of a single or a few CpG sites have been associated to complex phenotypes, because they are probably located in specific functional regions; in most cases, including gastric and colon cancer, rheumatoid arthritis and type 1 diabetes, these findings were always related to the regulation of the associated gene (Joensuu et al ., ; Yara et al ., ; Zhao et al ., ). Our results seem to be particularly attractive, because they show a fine remodeling of the methylation profile associated with the biological aging rather than to the chronological age and contribute to better clarify the molecular basis of the interindividual psychophysical vulnerability that characterizes the old age (Liu et al ., ; Bellizzi et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Methylation of the ribosomal RNA gene promoter is associated with aging and age‐related decline

et al. 2017

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SummaryThe transcription of ribosomal RNA genes (rDNA) is subject to epigenetic regulation, as it is abrogated by the methylation of CpG dinucleotides within their promoter region. Here, we investigated, through Sequenom platform, the age‐related methylation status of the CpG island falling into the rDNA promoter in 472 blood samples from 20‐ to 105‐year‐old humans and in different tissues (blood, heart, liver, kidney, and testis) of 15 rats 3–96 weeks old. In humans, we did not find a consistently significant correlation between CpG site methylation and chronological age. Furthermore, the methylation levels of one of the analyzed CpG sites were negatively associated with both cognitive performance and survival chance measured in a 9‐year follow‐up study. We consistently confirmed such result in a replication sample. In rats, the analysis of the homologous region in the tissues revealed the existence of increased methylation in old rats. rRNA expression data, in both humans and rats, were consistent with observed methylation patterns, with a lower expression of rRNA in highly methylated samples. As chronological and biological ages in rats of a given strain are likely to be much closer to each other than in humans, these results seem to provide the first evidence that epigenetic modifications of rDNA change over time according to the aging decline. Thus, the methylation profile of rDNA may represent a potential biomarker of aging.

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“…33,34 Higher frequency and intensity expression of DNMT1 in the DZ are consistent with the proliferative expansion known to occur in the DZ of GCs. 35 Recent studies have also demonstrated significant associations of DNMT1 with a higher Ki-67 score in other malignancies including breast cancer (n=348; P<0.0001), 36 colorectal cancer (n=14; P=0.014) and endometrial cancer (n=48; P=0.030), 37 while functional studies of Dnmt1-knockout or knockdown murine models have shown significant decrease of Ki-67-positive GC B cells 10 and other cell types. [38][39][40] These results indicate that the frequent coexpression of DNMT1 with Ki-67 in normal B cells appears to be maintained in DLBCL cases, and suggest that DNMT1 enables the proliferation of DLBCL cells in line with our observations of frequent DNMT1 expression in DLBCL mitotic cells as well as the established requirement of DNMT1 in cellular replication.…”

Section: Discussionmentioning

confidence: 99%

DNMT1 is predictive of survival and associated with Ki-67 expression in R-CHOP-treated diffuse large B-cell lymphomas

et al. 2017

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DNMT1 is a target of approved anti-cancer drugs including decitabine. However, the prognostic value of DNMT1 protein expression in R-CHOP-treated diffuse large B-cell lymphomas (DLBCLs) remains unexplored. Here we showed that DNMT1 was expressed in the majority of DLBCL cases (n = 209/230, 90.9%) with higher expression in germinal centre B-cell-like (GCB)-DLBCL subtype. Low and negative DNMT1 expression (20% cut-off, n = 33/230, 14.3%) was predictive of worse overall survival (OS; p < 0.001) and progression-free survival (PFS; p < 0.001). Nonetheless, of the 209 DNMT1 positive patients, 33% and 42% did not achieve 5-year OS and PFS, respectively, indicating that DNMT1 positive patients showed considerably heterogeneous outcomes. Moreover, DNMT1 was frequently expressed in mitotic cells and significantly correlated with Ki-67 or BCL6 expression (r = 0.60 or 0.44, respectively; p < 0.001). We demonstrate that DNMT1 is predictive of DLBCL patients' survival, and suggest that DNMT1 could be a DLBCL therapeutic target due to its significant association with Ki-67.

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Methyltransferase expression and tumor suppressor gene methylation in sporadic and familial colorectal cancer

Cited by 14 publications

References 63 publications

DNA Hypomethylation of miR-30a Mediated the Protection of Hypoxia Postconditioning Against Aged Cardiomyocytes Hypoxia/Reoxygenation Injury Through Inhibiting Autophagy

DNA Hypomethylation of miR-30a Mediated the Protection of Hypoxia Postconditioning Against Aged Cardiomyocytes Hypoxia/Reoxygenation Injury Through Inhibiting Autophagy

Methylation of the ribosomal RNA gene promoter is associated with aging and age‐related decline

DNMT1 is predictive of survival and associated with Ki-67 expression in R-CHOP-treated diffuse large B-cell lymphomas

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