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Calvo E.,Molecular Endocrinology and Oncology Research Center | Grzenda A.,Chromatin | Lomberk G.,Chromatin | Mathison A.,Chromatin | And 4 more authors.
BMC Molecular Biology | Year: 2014

Background: Krüppel-like factors (KLFs) are a group of master regulators of gene expression conserved from flies to human. However, scant information is available on either the mechanisms or functional impact of the coupling of KLF proteins to chromatin remodeling machines, a deterministic step in transcriptional regulation.Results and discussion: In the current study, we use genome-wide analyses of chromatin immunoprecipitation (ChIP-on-Chip) and Affymetrix-based expression profiling to gain insight into how KLF11, a human transcription factor involved in tumor suppression and metabolic diseases, works by coupling to three co-factor groups: the Sin3-histone deacetylase system, WD40-domain containing proteins, and the HP1-histone methyltransferase system. Our results reveal that KLF11 regulates distinct gene networks involved in metabolism and growth by using single or combinatorial coupling events.Conclusion: This study, the first of its type for any KLF protein, reveals that interactions with multiple chromatin systems are required for the full gene regulatory function of these proteins. © 2014 Calvo et al. Source

Guillaumond F.,Aix - Marseille University | Bidaut G.,Aix - Marseille University | Ouaissi M.,French Institute of Health and Medical Research | Servais S.,French Institute of Health and Medical Research | And 18 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

The malignant progression of pancreatic ductal adenocarcinoma (PDAC) is accompanied by a profound desmoplasia, which forces proliferating tumor cells to metabolically adapt to this new microenvironment. We established the PDAC metabolic signature to highlight the main activated tumor metabolic pathways. Comparative transcriptomic analysis identified lipid-related metabolic pathways as being the most highly enriched in PDAC, compared with a normal pancreas. Our study revealed that lipoprotein metabolic processes, in particular cholesterol uptake, are drastically activated in the tumor. This process results in an increase in the amount of cholesterol and an overexpression of the low-density lipoprotein receptor (LDLR) in pancreatic tumor cells. These findings identify LDLR as a novel metabolic target to limit PDAC progression. Here, we demonstrate that shRNA silencing of LDLR, in pancreatic tumor cells, profoundly reduces uptake of cholesterol and alters its distribution, decreases tumor cell proliferation, and limits activation of ERK1/2 survival pathway. Moreover, blocking cholesterol uptake sensitizes cells to chemotherapeutic drugs and potentiates the effect of chemotherapy on PDAC regression. Clinically, high PDAC Ldlr expression is not restricted to a specific tumor stage but is correlated to a higher risk of disease recurrence. This study provides a precise overview of lipid metabolic pathways that are disturbed in PDAC. We also highlight the high dependence of pancreatic cancer cells upon cholesterol uptake, and identify LDLR as a promising metabolic target for combined therapy, to limit PDAC progression and disease patient relapse. LDLR cholesterol pancreatic cancer metabolism gemcitabine . Source

Tomasini R.,French Institute of Health and Medical Research | Tomasini R.,Ontario Cancer Institute | Secq V.,French Institute of Health and Medical Research | Pouyet L.,French Institute of Health and Medical Research | And 10 more authors.
Cell Death and Differentiation | Year: 2013

The multiple isoforms of p73, a member of the p53 family, share the ability to modulate p53 activities but also have unique properties, leading to a complex and poorly understood functional network. In vivo, p73 isoforms have been implicated in tumor suppression (TAp73-/- mice), DNA damage (ΔNp73-/- mice) and development (p73-/- mice). In this study, we investigated whether TAp73 contributes to innate immunity and septic shock. In response to a lethal lipopolysaccharide (LPS) challenge, TAp73-/- mice showed higher blood levels of proinflammatory cytokines and greater mortality than their wild-type littermates. In vitro, TAp73 -/- macrophages exhibited elevated production of tumor necrosis factor alpha, interleukin-6 and macrophage inflammatory protein-2 as well as prolonged survival, decreased phagocytosis and increased major histocompatibility complex class II expression. Mice depleted of endogenous macrophages and reconstituted with TAp73-/- macrophages showed increased sensitivity to LPS challenge. These results suggest that macrophage polarization is altered in the absence of TAp73 such that maintenance of the M1 effector phenotype is prolonged at the expense of the M2 phenotype, thus impairing resolution of the inflammatory response. Our data indicate that TAp73 has a role in macrophage polarization and innate immunity, enhancing the action field of this important regulatory molecule. © 2013 Macmillan Publishers Limited All rights reserved. Source

Grasso D.,Aix - Marseille University | Garcia M.N.,Aix - Marseille University | Hamidi T.,Aix - Marseille University | Cano C.,Aix - Marseille University | And 4 more authors.
Cell Death and Differentiation | Year: 2014

Nuclear protein 1 (Nupr1), a small chromatin protein, has a critical role in cancer development, progression and resistance to therapy. Previously, we had demonstrated that Nupr1 cooperates with KrasG12D to induce pancreas intraepithelial neoplasias (PanIN) formation and pancreatic ductal adenocarcinoma development in mice. However, the molecular mechanisms by which Nupr1 influences Kras-mediated preneoplastic growth remain to be fully characterized. In the current study, we report evidence supporting a role for Nupr1 as a gene modifier of KrasG12D-induced senescence, which must be overcome to promote PanIN formation. We found that genetic inactivation of Nupr1 in mice impairs Kras-induced PanIN, leading to an increase in β-galactosidase-positive cells and an upregulation of surrogate marker genes for senescence. More importantly, both of these cellular and molecular changes are recapitulated by the results of mechanistic experiments using RNAi-based inactivation of Nupr1 in human pancreatic cancer cell models. In addition, the senescent phenotype, which results from Nupr1 inactivation, is accompanied by activation of the FoxO3a-Skp2-p27Kip1-pRb-E2F pathway in vivo and in vitro. Thus, combined, these results show, for the first time, that Nupr1 aids oncogenic Kras to bypass senescence in a manner that cooperatively promotes PanIN formation. Besides its mechanistic importance, this new knowledge bears medical relevance as it delineates early pathobiological events that may be targeted in the future as a means to interfere with the formation of preneoplastic lesions early during pancreatic carcinogenesis. © 2014 Macmillan Publishers Limited All rights reserved. Source

Cano C.E.,Aix - Marseille University | Hamidi T.,Aix - Marseille University | Garcia M.N.,Aix - Marseille University | Grasso D.,Aix - Marseille University | And 10 more authors.
Gut | Year: 2014

Background: Nuclear protein 1 (Nupr1) is a major factor in the cell stress response required for KrasG12D-driven formation of pancreatic intraepithelial neoplastic lesions (PanINs). We evaluated the relevance of Nupr1 in the development of pancreatic cancer. Methods: We investigated the role of Nupr1 in pancreatic ductal adenocarcinoma (PDAC) progression beyond PanINs in Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl (KIC) mice. Results: Even in the context of the second tumorigenic hit of Ink4a/Arf deletion, Nupr1 deficiency led to suppression of malignant transformation involving caspase 3 activation in premalignant cells of KIC pancreas. Only half of Nupr1-deficient;KIC mice achieved PDAC development, and incident cases survived longer than Nupr1wt;KIC mice. This was associated with the development of well-differentiated PDACs in Nupr1-deficient;KIC mice, which displayed enrichment of genes characteristic of the recently identified human classical PDAC subtype. Nupr1-deficient;KIC PDACs also shared with human classical PDACs the overexpression of the Kras-activation gene signature. In contrast, Nupr1wt;KIC mice developed invasive PDACs with enriched gene signature of human quasi-mesenchymal (QM) PDACs. Cells derived from Nupr1-deficient;KIC PDACs growth in an anchorage-independent manner in vitro had higher aldehyde dehydrogenase activity and overexpressed nanog, Oct-4 and Sox2 transcripts compared with Nupr1wt;KIC cells. Moreover, Nupr1-deficient and Nurpr1wt;KIC cells differed in their sensitivity to the nucleoside analogues Ly101-4b and WJQ63. Together, these findings show the pivotal role of Nupr1 in both the initiation and late stages of PDAC in vivo, with a potential impact on PDAC cell stemness. Conclusions: According to Nupr1 status, KIC mice develop tumours that phenocopy human classical or QM-PDAC, respectively, and present differential drug sensitivity, thus becoming attractive models for preclinical drug trials. Source

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