The de novo DNA methyltransferase DNMT3A in development and cancer

Chen, Bifeng; Chan, Wai‐Yee

doi:10.4161/epi.28324

Cited by 77 publications

(48 citation statements)

References 94 publications

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“…This observation presents interesting connections with our findings in the rat biocollection of cell lines, a significant decrease in the expression of Dnmt3b being observed between all preneoplastic and neoplastic cell lines, as well as between the PNsarc group and neoplastic cell lines. The different evolution observed in the human biocollection for the expression of this enzyme, while a common pattern of expression profile was observed in the two species for Dnmt3a , could also be explained by recent reports indicating that the two enzymes have overlapping functions and that their roles in cancers may be more complex than previously believed [58]. In our study, the final fall in expression of de novo Dnmt3a and Dnmt3b could be explained by the recent demonstration of downregulation after induction of EMT by TGFβ in lung cancer cells [59].…”

Section: Discussionmentioning

confidence: 81%

Characterization of preneoplastic and neoplastic rat mesothelial cell lines: the involvement of TETs, DNMTs, and 5-hydroxymethylcytosine

et al. 2016

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Malignant mesothelioma (MM) is one of the worst cancers in terms of clinical outcome, urging the need to establish and characterize new preclinical tools for investigation of the tumorigenic process, improvement of early diagnosis and evaluation of new therapeutic strategies. For these purposes, we characterized a collection of 27 cell lines established from F344 rats, after 136 to 415 days of induction with crocidolite asbestos administered intraperitoneally. Four mesotheliomas were distinguished from 23 preneoplastic mesothelial cell lines (PN) according to their propensity to generate tumors after orthotopic transplantation into syngeneic rats, their growth pattern, and the expression profile of three genes. PN cell lines were further discriminated into groups / subgroups according to morphology in culture and the expression profiles of 14 additional genes. This approach was completed by analysis of positive and negative immunohistochemical MM markers in the four tumors, of karyotype alterations in the most aggressive MM cell line in comparison with a PN epithelioid cell line, and of human normal mesothelial and mesothelioma cells and a tissue array. Our results showed that both the rat and human MM cell lines shared in common a dramatic decrease in the relative expression of Cdkn2a and of epigenetic regulators, in comparison with PN and normal human mesothelial cells, respectively. In particular, we identified the involvement of the relative expression of the Ten-Eleven Translocation (TET) family of dioxygenases and Dnmt3a in relation to the 5-hydroxymethylcytosine level in malignant transformation and the acquisition of metastatic potential.

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Section: Discussionmentioning

confidence: 81%

Characterization of preneoplastic and neoplastic rat mesothelial cell lines: the involvement of TETs, DNMTs, and 5-hydroxymethylcytosine

et al. 2016

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“…DNMT3A, is a de novo DNA methyltransferase belonging to the DNA Methyltransferase (DNMT) family, which plays an important role in the establishment of methylation patterns during early embryogenesis, and functions as an oncogene in human cancers (Chen and Chan, ). DNMT3A is a multi‐functional protein, the relationship between DNMT3A and cellular senescence has been reported as well.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the first demonstration in the present study that miR-194 significantly promotes the progression of cellular senescence further enlarges the knowledge of the effects of miR-194 on biological process. DNMT3A, is a de novo DNA methyltransferase belonging to the DNA Methyltransferase (DNMT) family, which plays an important role in the establishment of methylation patterns during early embryogenesis, and functions as an oncogene in human cancers (Chen and Chan, 2014). DNMT3A is a multi-functional protein, the relationship between DNMT3A and cellular senescence has been reported as well.…”

Section: Discussionmentioning

confidence: 99%

miR‐194 functions as a novel modulator of cellular senescence in mouse embryonic fibroblasts

Zhang

Zhu

et al. 2017

Cell Biology International

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MicroRNA-194 (miR-194), a typical p53 responsive miRNA, serves as a tumor suppressor similar as p53, and has been demonstrated to play an anti-proliferation role in various human cancers. In spite of the pivotal role of p53 during aging process, the knowledge of miR-194's contribution to cellular senescence is limited. We herein sought to explore the role of miR-194 in the replicative senescence and stress-induced senescence of mouse embryonic fibroblasts. Our results unraveled that, compared to young cells, miR-194 is highly expressed in senescent cells, and extra expression of miR-194 significantly triggers the replicative senescence of MEFs and H O -induced senescence of NIH/3T3 cells, while inhibition of miR-194 exhibited the opposite effect. We further unveiled that DNMT3A was a direct and authentic target of miR-194, which has been reported to be closely associated with cellular senescence. Taken together, our data suggest that miR-194 may significantly promote the development of cellular senescence in mouse embryonic fibroblasts, which potentially occurs through inhibiting the DNMT3A expression.

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“…In cancer, global DNA methylation patterns are altered, accompanied by CpG island hypermethylation and non-CpG island hypomethylation at specific gene promoters (9). This alteration is largely dependent on the action of de novo DNMT3A during early tumor progression (10). Notably, several inactivating mutations of DNMT3A in myeloid malignancies and loss of DNMT3A activity at advanced tumor stages were recently identified (11).…”

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confidence: 99%

SUV39H1/DNMT3A‐dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development

et al. 2018

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Melanoma is among the most aggressive and treatment-resistant human cancers. Aberrant histone H3 methylation at Lys 9 (H3K9) correlates with carcinogenic gene silencing, but the significance of suppressor of variegation 3-9 homolog 1 (SUV39H1), an H3K9-specific methyltransferase, in melanoma initiation and progression remains unclear. Here, we show that SUV39H1-mediated H3K9 trimethylation facilitates retinoblastoma ( RB) 1 promoter CpG island methylation by interacting with DNA methyltransferase 3A and decreasing RB mRNA and protein in melanoma cells. Reduced RB abundance, in turn, impairs E2F1 transcriptional inhibition, leading to increased peptidyl-prolyl cis-trans isomerase never-in-mitosis A (NIMA)-interacting 1 (PIN1) levels, human keratinocyte neoplastic cell transformation, and melanoma tumorigenesis via enhanced rapidly accelerated fibrosarcoma 1(RAF1)-MEK-ERK signaling pathway activation. In a synergistic model with B16-F1 murine melanoma cells, SUV39H1 and PIN1 overexpression increased melanoma growth, which was abrogated by their inhibition in SUV39H1-overexpressing B16-F1 mice. SUV39H1 also positively correlated with PIN1 expression in human melanoma. Our studies establish SUV39H1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.-Kim, G., Kim, J.-Y., Lim, S.-C., Lee, K. Y., Kim, O., Choi, H. S. SUV39H1/DNMT3A-dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development.

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The de novo DNA methyltransferase DNMT3A in development and cancer

Cited by 77 publications

References 94 publications

Characterization of preneoplastic and neoplastic rat mesothelial cell lines: the involvement of TETs, DNMTs, and 5-hydroxymethylcytosine

Characterization of preneoplastic and neoplastic rat mesothelial cell lines: the involvement of TETs, DNMTs, and 5-hydroxymethylcytosine

miR‐194 functions as a novel modulator of cellular senescence in mouse embryonic fibroblasts

SUV39H1/DNMT3A‐dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development

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