Targeting the H3K4 Demethylase KDM5B Reprograms the Metabolome and Phenotype of Melanoma Cells.
J Invest Dermatol
; 139(12): 2506-2516.e10, 2019 12.
Article
em En
| MEDLINE
| ID: mdl-31229500
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
/
Neoplasias Cutâneas
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RNA Neoplásico
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Proteínas Nucleares
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Histonas
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Regulação Neoplásica da Expressão Gênica
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Metaboloma
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Histona Desmetilases com o Domínio Jumonji
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Melanoma
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Invest Dermatol
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Alemanha