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DOI: 10.1055/s-0038-1677232
Metabolic Changes upon Inhibition of the Lysine-Specific-Demethylase-1 (LSD1) in Hepatocellular Carcinoma
Publikationsverlauf
Publikationsdatum:
04. Januar 2019 (online)
Hepatocellular carcinoma (HCC) represents the final stage of a wide variety of hepatic disorders. Numerous hepatitis B infections worldwide and a rising number of non-alcoholic-fat-liver-diseases in industrialized countries make HCC a global health issue. Nevertheless, systemic therapy options are still lacking and to ensure suitable treatment the development of new drugs is essential. Current research indicates that epigenetic alterations play an important role in the most malignant entities and might be targets for novel therapeutical options. The epigenetic modifier LSD1 was shown to be overexpressed in many cancer types, including HCC. LSD1 demethylates histone 3 at lysine 4 and 9 (H3K4/9) and causes either transcriptional repression or activation, respectively. In the present study the impact of the novel LSD1 inhibitor HCI-2509 was tested on HCC cells.
Gene expression profiling using ultra-deep RNA-sequencing revealed that in different HCC cell lines not only mediators of the cell cycle but also the expression of metabolism associated genes was strongly affected in response to pharmacological LSD1 inhibition. Expression alterations were observed in three major metabolic pathways: the glycolysis, the citric acid cycle and the mitochondrial electron transport chain. Importantly, the data indicated a consistent and highly pronounced decrease of transcripts encoding various subunits of the mitochondrial respiratory chain complex I. Comparative fluorescence microscopy of LSD1 inhibited versus non-treated cells revealed changes in regard to the mitochondrial morphology and their distribution in the cytosol. Flow cytometry based quantification proved a decrease of the mitochondrial membrane potential in response to inhibition of the demethylase by HCI-2509, indicating mitochondrial dysfunction. In order to get a more detailed depiction of the respiratory situation upon LSD1 inhibition a metabolic analysis was conducted in various LSD1 inhibited HCC cells, confirming the dysfunction of mitochondrial oxidative phosphorylation processes. The cell lines showed a reduced baseline in the oxygen consumption rate, as well as a lower ATP production and respiratory capacity after HCI-2509 treatment.
Thus, our findings show that LSD1 inhibition leads to an impaired cellular respiration and ATP depletion caused by a dysregulation of the electron transport chain complex I. Hence, the cancer cell metabolism is influenced in a disadvantageous way and the malignant cell is not able to serve its energetic demands, necessary for rapid cell proliferation and invasion. Altogether this data emphasizes the value of HCI-2509 as a novel antineoplastic therapeutic agent, affecting HCC cell proliferation not only by cell cycle interruption, but also by energetic restriction.
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