DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors

Sin‐Chan, Patrick; Huang, Annie

doi:10.1517/14728222.2014.938052

Cited by 15 publications

(7 citation statements)

References 17 publications

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“…Enrichment of 5-carboxylcytosine (5caC) and increased TET1 expression, which are involved in active DNA demethylation, are epigenetic hallmarks of EPN and SHH MB (Ramsawhook et al, 2017). Hypermethylated genes in EPN converge on defined sets of embryonic stem cell (ESC) targets, suggesting a linkage, mediated by epigenetic programming, between embryonic development and pediatric brain cancer (Sin-Chan and Huang, 2014;Mack et al, 2016).…”

Section: Epigenetic Basis Of Pediatric Brain Cancersmentioning

confidence: 99%

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

Perla

Fratini

Cardoso

et al. 2020

Front. Cell Dev. Biol.

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Brain cancers are the leading cause of cancer-related deaths in children. Biological changes in these tumors likely include epigenetic deregulation during embryonal development of the nervous system. Histone acetylation is one of the most widely investigated epigenetic processes, and histone deacetylase inhibitors (HDACis) are increasingly important candidate treatments in many cancer types. Here, we review advances in our understanding of how HDACis display antitumor effects in experimental models of specific pediatric brain tumor types, i.e., medulloblastoma (MB), ependymoma (EPN), pediatric high-grade gliomas (HGGs), and rhabdoid and atypical teratoid/rhabdoid tumors (ATRTs). We also discuss clinical perspectives for the use of HDACis in the treatment of pediatric brain tumors.

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Section: Epigenetic Basis Of Pediatric Brain Cancersmentioning

confidence: 99%

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

Perla

Fratini

Cardoso

et al. 2020

Front. Cell Dev. Biol.

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“…Importantly, hypermethylated genes converged upon embryonic stem cell (ESC) targets regulated by the Polycomb Repressor Complex 2 (PRC2), suggesting that epigenomic alterations could be disrupting cell state and differentiation programs important to ependymoma development. A link between ESC programs and cancer is further demonstrated in the embryonal brain tumor ETMR, which harbors a fusion between a highly amplified microRNA cluster (C19MC) and TTYH1 (Tweety family member 1) 28, 82, 83 . A downstream consequence of the fusion is aberrant overexpression of a novel DNA methyltransferase 3B ( DNMT3B ) isoform normally and exclusively expressed in the first weeks of neural tube development.…”

Section: Introductionmentioning

confidence: 99%

An epigenetic gateway to brain tumor cell identity

et al. 2015

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Precise targeting of genetic lesions alone has been insufficient to extend brain tumor patient survival. Brain cancer cells are diverse in their genetic, metabolic, and microenvironmental compositions, accounting for their phenotypic heterogeneity and disparate responses to therapy. These factors converge at the level of the epigenome, representing a unified node that can be disrupted by pharmacologic inhibition. Aberrant epigenomes define many childhood and adult brain cancers, as demonstrated by widespread changes to DNA methylation patterns, redistribution of histone marks, and disruption of chromatin structure. In this review, we describe the convergence of genetic, metabolic, and micro-environmental factors upon mechanisms of epigenetic deregulation in brain cancer. We discuss how aberrant epigenetic pathways identified in brain tumors affect cell identity, cell state, and neoplastic transformation, in addition to the potential to exploit these alterations as novel therapeutic strategies for the treatment of brain cancer.

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“…Over-expression of DNMTs has been described in several human tumour types, including lymphomas, liver, prostate, colorectal, breast, lung, pancreatic and endometrial cancer [13–18], and is generally associated with a more aggressive phenotype, indicating that DNMT1, 3A and 3B likely act as oncogenes [19]. Recent evidences suggest that a deregulation of the de novo DNMT enzymes contributes to the development of paediatric brain tumours [20]. Silencing of tumour suppressor genes (TSGs) by promoter CpG island hypermethylation seems to be the most probable mechanism involved in the process of carcinogenesis linked to epigenetic events.…”

Section: Introductionmentioning

confidence: 99%

DNMT3Bin vitroknocking-down is able to reverse embryonal rhabdomyosarcoma cell phenotype through inhibition of proliferation and induction of myogenic differentiation

et al. 2016

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Aberrant DNA methylation has been frequently observed in many human cancers, including rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children. To date, the expression and function of the de novo DNA methyltransferase (DNMT) 3B in RMS have not yet been investigated. Our study show for the first time a significant up-regulation of DNMT3B levels in 14 RMS tumour samples and 4 RMS cell lines in comparison to normal skeletal muscle. Transfection of RD and TE671 cells, two in vitro models of embryonal RMS (ERMS), with a synthetic DNMT3B siRNA decreased cell proliferation by arresting cell cycle at G1 phase, as demonstrated by the reduced expression of Cyclin B1, Cyclin D1 and Cyclin E2, and by the concomitant up-regulation of the checkpoint regulators p21 and p27. DNMT3B depletion also impaired RB phosphorylation status and decreased migratory capacity and clonogenic potential. Interestingly, DNMT3B knock-down was able to commit ERMS cells towards myogenic terminal differentiation, as confirmed by the acquisition of a myogenic-like phenotype and by the increased expression of the myogenic markers MYOD1, Myogenin and MyHC. Finally, inhibition of MEK/ERK signalling by U0126 resulted in a reduction of DNMT3B protein, giving evidence that DNMT3B is a down-stream molecule of this oncogenic pathway.Taken together, our data indicate that altered expression of DNMT3B plays a key role in ERMS development since its silencing is able to reverse cell cancer phenotype by rescuing myogenic program. Epigenetic therapy, by targeting the DNA methylation machinery, may represent a novel therapeutic strategy against RMS.

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DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors

Cited by 15 publications

References 17 publications

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

An epigenetic gateway to brain tumor cell identity

DNMT3Bin vitroknocking-down is able to reverse embryonal rhabdomyosarcoma cell phenotype through inhibition of proliferation and induction of myogenic differentiation

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