PO-263 Epigenetic modulation of cell metabolism and its effects on cell survival in melanoma

Introduction Melanoma is an aggressive tumour with a median survival of only 6–12 month after occurrence of metastasis. In detail, one key factor of drug resistance mechanism in melanoma pathogenesis is cell heterogeneity. A defined cell subpopulation of slow cycling cells marked by a high histone demethylase JARID1B expression are therapy resistant and are most likely responsible for tumour repopulation. Moreover, cells with a slow cycling phenotype are described to modulate metabolism under targeted therapy. Therefore, the aim of my thesis is to characterise metabolic ‘hubs’ within metabolic landscaping analysis of melanoma cells. Material and methods We induced JARID1B low and JARID1B high phenotypes in WM3734 melanoma cells via shRNA-mediated knockdown and Doxycyclin-inducible Tet3G-Overexpression and prepared for a subpopulation-specific LC-HRMS based metabolomics landscaping analysis. Additionally, we investigated if chemical H3K4 demethylase inhibition could be used to specifically target the JARID1B-driven malignant metabolic phenotype in melanoma cells. Results and discussions JARID1B high expressing melanoma cells show upregulated metabolites of glutathione-redox-system and pentose phosphate pathway. Moreover, several upregulated metabolites in JARID1B high melanoma cells confirm existing data stating that those tumour cells do not follow the Warburg effect, but rather depend on mitochondrial OXPHOS to gain ATP and maintain a multi-resistant phenotype. Furthermore, a treatment with H3K4 demethylase inhibitors modulates the detected active metabolic pathways in melanoma cells functionally and also impairs cell proliferation and invasion capacity. Conclusion Our present metabolic landscaping analysis unravelled heterogeneous metabolic profiles in melanoma pointing to a possible relevance for therapy resistance of distinct melanoma cell subpopulations. In detail, we could profile the metabolome of multi-drug resistant JARID1B high melanoma cells including their underlying enzymatic hubs. To overcome drug resistance in future, such hubs could be either directly targeted or indirectly by inhibiting their epigenetic regulators.