Scientific publication

Targeting the H3K4 Demethylase KDM5B Reprograms the Metabolome and Phenotype of Melanoma Cells

Publication from Health
Bioanalytik und Metabolomics

Vogel, Felix C. E., Natalie Bordag, Elmar Zügner, Marija Trajkovic-Arsic, Heike Chauvistré, Batool Shannan, Renáta Váraljai, Susanne Horn, Christoph Magnes, Jens Siveke, Dirk Schadendorf, Alexander Roesch

Journal of Investigative Dermatology , 6/2019


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.

Keywords: mass spectrometry