Tumor induction by disruption of the Dnmt1, PCNA and UHRF1 interactions.

The low level of DNA methylation in tumors compared to the level of DNA methylation in their normal-tissue counterparts or global DNA hypomethylation was one of the first epigenetic alterations to be found in human cancer^1,2^. While the contribution of genome hypomethylation in cancer development and progression is explained by several mechanisms: chromosomal instability, loss of imprinting, and reactivation of transposable elements^3, 4^, the molecular causes of genome hypomethylation remain unclear. Indeed, despite the central roles of the DNA methyltransferases (Dnmts) in the establishment and maintenance of the DNA methylation, no clear consensus appears between the reduction of the Dnmts expression and the genome hypomethylation in human cancers^5^. Nevertheless, the cancer-associated genome hypomethylation could be explained by the disruption of interactions existing between Dnmts and the DNA replication and DNA repair proteins because these interactions play a crucial role in the DNA methylation in mammalian cells^6-8^. We here demonstrate that the disruption of the Dnmt1/PCNA and Dnmt1/UHRF1 interactions induce the genome hypomethylation and act as oncogenic factors promoting the tumorigenesis. We also identify the Akt- and/or PKC-mediated phosphorylations of Dnmt1 as both initiators of these disruptions and as a hallmark conferring poor prognosis in glioma patients

ABT-737 and/or folate reverse the PDGF-induced alterations in the mitochondrial apoptotic pathway in low-grade glioma patients

Elevated activation of the platelet-derived growth factor (PDGF) pathway, apoptosis evasion phenotype, and global DNA hypomethylation are hallmarks frequently observed in cancers, such as in low-grade glioma (LGG). However, the orchestration of these malignant functions is not fully elucidated in LGG. Our study reveals that the co-presence of these hallmarks in the same LGG is frequent and confers poor prognosis in patients with LGG. Our data also indicate that the apoptosis evasion phenotype of these cells harboring a hypomethylation-induced activation of the PDGF pathway is associated with a hypomethylation of the bcl-xl and bcl-w genes and the phosphorylation and/or downregulation of three major pro-apoptotic BH3-only proteins: PUMA, Bad, and Bim. Consistent with this, we demonstrate that the use of folate, a DNA-methylating agent, promotes the reprogramming of the sensitivity of glioma cells to ABT-737/etoposide-induced apoptosis and reduces the dose of ABT-737 required to promote etoposide-induced apoptosis. This work supports the idea that the inclusion of folate and/or ABT-737 could be a promising adjuvant in the design of anti-glioma therapeutic protocols in clinical studies

Epigenetic protein complexes: the adequate candidates for the use of a new generation of epidrugs in personalized and precision medicine in cancer

International audienceUntil recently, drug development in oncology was focused on treating most patients for a specific cancer type without taking in account the heterogeneity between these patients in term of response to treatment. Therefore, this type of broad treatment approach excludes the treatment of patient not responding to disease-specific common drugs. In this review, we focus on the different types of epigenetic drugs currently used as DNA methylation inhibitor agents and their limits in patient care due to their lack of specificity. We also highlight the emergence of a new type of epidrug with higher target specificity due to their original mechanism of action: the disruption of protein complexes involved in the epigenetic modifications

Specific inhibition of DNMT1/CFP1 reduces cancer phenotypes and enhances chemotherapy effectiveness

International audienceAim: DNA methylation is a fundamental biologic process of genomes and is a candidate for pharmacological manipulation that might have important therapeutic advantages. Thus, DNA methyltransferases (DNMTs) appear to be ideal targets for drug intervention. Materials & methods: To develop a new generation of DNMT inhibitor, we analyzed the ability of peptides to selectively inhibit certain DNMT1-incuding complexes. Results: Our study demonstrates that the disruption of DNMT1/CFP1-including complexes increases the efficiency of chemotherapeutic treatment on established tumors in mice. Conclusion: Our data opens a promising and innovative alternative to the development of DNMT inhibitor

From 1957 to Nowadays: A Brief History of Epigenetics

International audienceDue to the spectacular number of studies focusing on epigenetics in the last few decades, and particularly for the last few years, the availability of a chronology of epigenetics appears essential. Indeed, our review places epigenetic events and the identification of the main epigenetic writers, readers and erasers on a historic scale. This review helps to understand the increasing knowledge in molecular and cellular biology, the development of new biochemical techniques and advances in epigenetics and, more importantly, the roles played by epigenetics in many physiological and pathological situations

Diuron modulates the DNA methylation status of the ILT7 and TRAIL/TNFSF10 genes and decreases the killing activity of plasmacytoid dendritic cells

International audienceBackground: Plasmacytoid dendritic cell (pDC) is described as the Swiss knife of immune system. Thus, the understanding of aberrant epigenetic reprogramming of genes governing the pDC functionality by pollutants appears such as an attractive research point. Results: Our study has investigated the effect of Diuron (an herbicide) on the pDC-killing activity towards cancer cells. Thus, we observed that the Diuron exposure of pDC promotes a context of global DNA hypomethylation, which is associated with a phenotype of decrease of the killing activity of pDC towards cancer cells. At molecular level, our data associated the Diuron-induced global DNA hypomethylation with the elevated expression of TET2, an epigenetic player involved in DNA demethylation processes, and the decrease of the pDC-killing activity with the decrease of TRAIL expression and the increase of ILT7 expression. Conclusions: Thus, our article reports that a pollutant (Diuron) induces an epigenetic reprogramming of a subtype of immune cell (pDC), which decreases its killing activity towards tumors cells. In some context, this mechanism might be conducive to the initiation of pathologies. which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made

TOM20-mediated transfer of Bcl2 from ER to MAM and mitochondria upon induction of apoptosis

International audienceIn this work, we have explored the subcellular localization of Bcl2, a major antiapoptotic protein. In U251 glioma cells, we found that Bcl2 is localized mainly in the ER and is translocated to MAM and mitochondria upon induction of apoptosis; this mitochondrial transfer was not restricted to the demonstrator cell line, even if cell-specific modulations exist. We found that the Bcl2/mitochondria interaction is controlled by TOM20, a protein that belongs to the protein import machinery of the mitochondrial outer membrane. The expression of a small domain of interaction of TOM20 with Bcl2 potentiates its anti-apoptotic properties, which suggests that the Bcl2-TOM20 interaction is proapoptotic. The role of MAM and TOM20 in Bcl2 apoptotic mitochondrial localization and function has been confirmed in a yeast model in which the ER-mitochondria encounter structure (ERMES) complex (required for MAM stability in yeast) has been disrupted. Bcl2-TOM20 interaction is thus an additional player in the control of apoptosis

Control of glioma cell death and differentiation by PKM2–Oct4 interaction

International audienceGlioma stem cells are highly resistant to cell death and as such are supposed to contribute to tumor recurrence by eluding anticancer treatments. Here, we show that spheroids that contain rat neural stem cells (NSCs) or rat glioma stem cells (cancer stem cells, CSCs) express isoforms 1 and 2 of pyruvate kinase (PKM1 and PKM2); however, the expression of PKM2 is considerably higher in glioma spheroids. Silencing of PKM2 enhances both apoptosis and differentiation of rat and human glioma spheroids. We establish that PKM2 was implicated in glioma spheroid differentiation through its interaction with Oct4, a major regulator of self-renewal and differentiation in stem cells. The small molecule Dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, increases the amount of PKM2/Oct4 complexes and thus inhibited Oct4-dependent gene expression. Taken together, our results highlight a new molecular pathway through which PKM2 can manage gliomagenesis via the control of glioma stemness by Oct4