miR-221/222 Target the DNA Methyltransferase MGMT in Glioma Cells

Quintavalle, Cristina; Mangani, Davide; Roscigno, Giuseppina; Romano, Giulia; Díaz‐Lagares, Ángel; Iaboni, Margherita; Donnarumma, Elvira; Fiore, Danilo; Marinis, Pasqualino De; Soini, Ylermi; Esteller, Manel; Condorelli, Gerolama

doi:10.1371/journal.pone.0074466

Cited by 88 publications

(70 citation statements)

References 35 publications

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“…Recent studies addressed a further level of MGMT regulation through direct binding of specific miRNAs to the 3'-UTR of MGMT transcripts, which may lead to decreased mRNA stability and/or reduced protein translation [47]. Distinct miRNAs that have been implicated as direct regulators of MGMT expression include miR-181b [48,49], miR-181d [49], mir221/222 [50], as well as miR-767-3p and miR-648 [47]. Thus, also aberrant expression of miRNAs may contribute to the variable MGMT expression values observed in MGMTunmethylated tumors (Fig.…”

Section: Regulation Of Expression and Function Of Mgmtmentioning

confidence: 99%

MGMT testing—the challenges for biomarker-based glioma treatment

et al. 2014

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Many patients with malignant gliomas do not respond to alkylating agent chemotherapy. Alkylator resistance of glioma cells is mainly mediated by the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). Epigenetic silencing of the MGMT gene by promoter methylation in glioma cells compromises this DNA repair mechanism and increases chemosensitivity. MGMT promoter methylation is, therefore, a strong prognostic biomarker in paediatric and adult patients with glioblastoma treated with temozolomide. Notably, elderly patients (>65-70 years) with glioblastoma whose tumours lack MGMT promoter methylation derive minimal benefit from such chemotherapy. Thus, MGMT promoter methylation status has become a frequently requested laboratory test in neuro-oncology. This Review presents current data on the prognostic and predictive relevance of MGMT testing, discusses clinical trials that have used MGMT status to select participants, evaluates known issues concerning the molecular testing procedure, and addresses the necessity for molecular-context-dependent interpretation of MGMT test results. Whether MGMT promoter methylation testing should be offered to all individuals with glioblastoma, or only to elderly patients and those in clinical trials, is also discussed. Justifications for withholding alkylating agent chemotherapy in patients with MGMT-unmethylated glioblastomas outside clinical trials, and the potential role for MGMT testing in other gliomas, are also discussed. What is the role for MGMT testing in other gliomas? The answers to these issues depend not only on data from controlled clinical trials, but also on the availability of alternative treatment options to alkylating agents treatment, as well as on the access to molecular testing and its sensitivity and specificity.

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Section: Regulation Of Expression and Function Of Mgmtmentioning

confidence: 99%

MGMT testing—the challenges for biomarker-based glioma treatment

et al. 2014

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“…Specific epigenetic mechanisms have been identified as responsible to activate Notch signaling in different malignancies with no detectable Notch genomic abnormalities (Wong et al, 2011). Among them, CpG islands methylation at both coding genes and microRNAs have been associated with CTCLs but also with other types of cancer (Sandoval et al, 2015;Esteller, 2008;Quintavalle et al, 2013). Promoter DNA methylation is a general epigenetic mechanism that plays a central role in the coordination of gene transcription in healthy normal cells.…”

Section: Introductionmentioning

confidence: 99%

Notch1 Pathway Activation Results from the Epigenetic Abrogation of Notch-Related MicroRNAs in Mycosis Fungoides

Gallardo

Sandoval

Díaz‐Lagares

et al. 2015

Journal of Investigative Dermatology

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Notch is a family of transmembrane receptors that participate in the regulation of cell differentiation, proliferation, and stemness. Notch pathway activation has also been found associated with different human cancers including primary cutaneous T-cell lymphomas (CTCL). The elucidation of the mechanisms driving Notch activation in these particular diseases has remained elusive. Here we studied the possibility that DNA methylation at Notch pathway gene promoters and/or deregulation of Notch-associated microRNAs contribute to activate Notch in mycosis fungoides (MF). By genome-wide DNA methylation analysis, we failed to detect any consistent methylation at the Notch1, the Notch-ligand Jagged1, or the Notch-target Hes1 gene promoters, but found a significant methylation of the Notch-related microRNAs, in particular miR-200c and miR-124. Downregulation of miR-200c is associated with overexpression of Jagged1, concomitant to Notch1 activation. CTCL cell lines were infected with lentiviral vector encoding for miR-200c and ectopic expression of miR-200c in CTCL lines resulted in Jagged1 protein downregulation associated with a reduction in the levels of active Notch1. Our study deciphers an epigenetic mechanism regulating the Notch pathway in (MF) that might contribute to the future design of more specific therapeutic strategies.

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“…3). Some miRs modulate TMZ sensitivity in vitro (59,64,(71)(72)(73) and have been proposed to predict either the response to chemoradiation in GBM patients (73,74) or patient outcome in different GBM subtypes (75). Based on the characterization of genetically-engineered mouse models, Squatrito et al (87) provided evidence that the ATM/CHK2/p53 pathway operates as a tumor suppressor in the brain.…”

mentioning

confidence: 99%

DNA repair mechanisms and their clinical impact in glioblastoma

Erasimus

Gobin

Niclou

et al. 2016

Mutation Research/Reviews in Mutation Research

148

105

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Despite surgical resection and genotoxic treatment with ionizing radiation and the DNA alkylating agent temozolomide, glioblastoma remains one of the most lethal cancers, due in great part to the action of DNA repair mechanisms that drive resistance and tumor relapse. Understanding the molecular details of these mechanisms and identifying potential pharmacological targets have emerged as vital tasks to improve treatment. In this review, we introduce the various cellular systems and animal models that are used in studies of DNA repair in glioblastoma. We summarize recent progress in our knowledge of the pathways and factors involved in the removal of DNA lesions induced by ionizing radiation and temozolomide. We introduce the therapeutic strategies relying on DNA repair inhibitors that are currently being tested in vitro or in clinical trials, and present the challenges raised by drug delivery across the blood brain barrier as well as new opportunities in this field. Finally, we review the genetic and epigenetic alterations that help shape the DNA repair makeup of glioblastoma cells, and discuss their potential therapeutic impact and implications for personalized therapy.

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miR-221/222 Target the DNA Methyltransferase MGMT in Glioma Cells

Cited by 88 publications

References 35 publications

MGMT testing—the challenges for biomarker-based glioma treatment

MGMT testing—the challenges for biomarker-based glioma treatment

Notch1 Pathway Activation Results from the Epigenetic Abrogation of Notch-Related MicroRNAs in Mycosis Fungoides

DNA repair mechanisms and their clinical impact in glioblastoma

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