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SHR Neuro Krebs Kardio Lipid

Vogel, FCE; Bordag, N; Zügner, E; Trajkovic-Arsic, M; Chauvistré, H; Shannan, B; Váraljai, R; Horn, S; Magnes, C; Thomas Siveke, J; Schadendorf, D; Roesch, A.
Targeting the H3K4 Demethylase KDM5B Reprograms the Metabolome and Phenotype of Melanoma Cells.
J Invest Dermatol. 2019; 139(12):2506-2516
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Autor/innen der Med Uni Graz:
Bordag Natalie
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Abstract:
Melanoma cells shift between epigenetic-metabolic states to adapt to stress and, particularly, to drugs. Here, we unraveled the metabolome of an H3K4 demethylase (KDM5B/JARID1B)-driven melanoma cell phenotype that is known to be multidrug resistant. We set up a fast protocol for standardized, highly sensitive liquid chromatography-high resolution mass spectrometry analyzing stably controlled KDM5B expression by RNAi or doxycycline-induced overexpression. Within the KDM5B-dependent metabolome, we found significant and highly specific regulation of 11 intracellular metabolites. Functionally, overexpression of KDM5B in melanoma cells led to broadening of their oxidative metabolism from mainly glutamine-dependent to additionally glucose- and fatty acid-utilizing, upregulation of the pentose phosphate pathway as a source of antioxidant NADPH, and maintenance of a high ratio of reduced to oxidized glutathione. Histone lysine demethylase inhibition (GSK-J1, 2,4-PDCA) decreased colony formation and invasion in three-dimensional models. Thus, targeting KDM5B could represent an alternative way of modulating the metabolome and malignant cell behavior in melanoma. Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

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