Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition
Marco Sciacovelli,
Emanuel Gonçalves,
Timothy Isaac Johnson,
Vincent Roberto Zecchini,
Ana Sofia Henriques da Costa,
Edoardo Gaude,
Alizee Vercauteren Drubbel,
Sebastian Julian Theobald,
Sandra Riekje Abbo, et al.
Mutations of the tricarboxylic acid cycle enzyme fumarate hydratase cause hereditary leiomyomatosis and renal cell cancer. Fumarate hydratase-deficient renal cancers are highly aggressive and metastasize even when small, leading to a very poor clinical outcome. Fumarate, a small molecule metabolite that accumulates in fumarate hydratase-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite. Fumarate has been shown to inhibit α-ketoglutarate-dependent dioxygenases that are involved in DNA and histone demethylation. However, the link between fumarate accumulation, epigenetic changes, and tumorigenesis is unclear. Here we show that loss of fumarate hydratase and the subsequent accumulation of fumarate in mouse and human cells elicits an epithelial-to-mesenchymal-transition (EMT), a phenotypic switch associated with cancer initiation, invasion, and metastasis. We demonstrate that fumarate inhibits Tet-mediated demethylation of a regulatory region of the antimetastatic miRNA cluster mir-200ba429, leading to the expression of EMT-related transcription factors and enhanced migratory properties. These epigenetic and phenotypic changes are recapitulated by the incubation of fumarate hydratase-proficient cells with cell-permeable fumarate. Loss of fumarate hydratase is associated with suppression of miR-200 and the EMT signature in renal cancer and is associated with poor clinical outcome. These results imply that loss of fumarate hydratase and fumarate accumulation contribute to the aggressive features of fumarate hydratase-deficient tumours.
ECM-Regulator timp Is Required for Stem Cell Niche Organization and Cyst Production in the Drosophila Ovary
John R. Pearson,
Federico Zurita,
Laura Tomás-Gallardo,
Alfonsa Díaz-Torres,
María Del Carmen Díaz de la Loza,
Kristian Franze,
María D. Martín-Bermudo,
Acaimo González-Reyes
PLoS genetics
12
(1)
e1005763
(2016)
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The extracellular matrix (ECM) is a pivotal component adult tissues and of many tissue-specific stem cell niches. It provides structural support and regulates niche signaling during tissue maintenance and regeneration. In many tissues, ECM remodeling depends on the regulation of MMP (matrix metalloproteinase) activity by inhibitory TIMP (tissue inhibitors of metalloproteinases) proteins. Here, we report that the only Drosophila timp gene is required for maintaining the normal organization and function of the germline stem cell niche in adult females. timp mutant ovaries show reduced levels of both Drosophila Collagen IV α chains. In addition, tissue stiffness and the cellular organization of the ovarian niche are affected in timp mutants. Finally, loss of timp impairs the ability of the germline stem cell niche to generate new cysts. Our results demonstrating a crucial role for timp in tissue organization and gamete production thus provide a link between the regulation of ECM metabolism and tissue homeostasis.
Brain tissue stiffness is a sensitive marker for acidosis
Kathrin Holtzmann,
Helene O. B. Gautier,
Andreas F. Christ,
Jochen Guck,
Ragnhildur Thora Karadottir,
Kristian Franze
JOURNAL OF NEUROSCIENCE METHODS
271
50-54
(2016)
| Journal
Background: Carbon dioxide overdose is frequently used to cull rodents for tissue harvesting. However, this treatment may lead to respiratory acidosis, which potentially could change the properties of the investigated tissue.<br> New method: Mechanical tissue properties often change in pathological conditions and may thus offer a sensitive generic readout for changes in biological tissues with clinical relevance. In this study, we performed force-indentation measurements with an atomic force microscope on acute cerebellar slices from adult rats to test if brain tissue undergoes changes following overexposure to CO2 compared to other methods of euthanasia.<br> Results: The pH significantly decreased in brain tissue of animals exposed to CO2. Concomitant with the drop in pH, cerebellar grey matter significantly stiffened. Tissue stiffening was reproduced by incubation of acute cerebellar slices in acidic medium.<br> Comparison with existing methods: Tissue stiffness provides an early, generic indicator for pathophysiological changes in the CNS. Atomic force microscopy offers unprecedented high spatial resolution to detect such changes.<br> Conclusions: Our results indicate that the stiffness particularly of grey matter strongly correlates with changes of the pH in the cerebellum. Furthermore, the method of tissue harvesting and preparation may not only change tissue stiffness but very likely also other physiologically relevant parameters, highlighting the importance of appropriate sample preparation. (C) 2016 The Authors. Published by Elsevier B.V.
Kontakt
Abteilung Neuronale Mechanik Prof. Kristian Franze Principal Investigator
Max-Planck-Zentrum für Physik und Medizin Kussmaulallee 2 91054 Erlangen
