Targeting the H3K4 demethylase KDM5B reprograms the metabolome and phenotype of melanoma cells.

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, which is known to be multi-drug resistant. We set up a fast protocol for standardized, high 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 anti-oxidant NADPH, and maintenance of a high GSH/GSSG ratio. KDM inhibition (GSK-J1, 2.4-PDCA) decreased colony formation and invasion in 3D models. Thus, targeting KDM5B could represent an alternative way of modulating the metabolome and malignant cell behavior in melanoma.