A comprehensive characterization of the dehydrogenase-reductase DHRS2 and its involvement in histone deacetylase inhibition.

BACKGROUND

Being implicated during tumor migration, invasion, clonogenicity, and proliferation, the nicotinamide adenine dinucleotide (NAD) / -phosphate (NADP)-dependent dehydrogenase / reductase member 2 (DHRS2) has been considered to be induced upon inhibition of histone deacetylases (HDACi). In this brief report, we evaluated the current knowledge on the underlying mechanisms of the (epi)genetic regulation of DHRS2, as well as its function during tumor progression.

METHODS

DHRS2 was evaluated on mRNA- and protein-level upon treatment with HDACi by means of qRT-PCR and western blot analyses, respectively. Re-analysis of RNA-sequencing data gained insight into specific DHRS2 isoforms, while re-analysis of ATAC-sequencing data enabled the analysis of chromatin accessibility at the DHRS2 locus. Further examination of the energy- and lipid metabolism of HDACi-treated urologic tumor cells was performed using liquid chromatography-mass spectrometry.

RESULTS

Enhanced DHRS2 expression levels upon HDACi treatment were directly linked to a hyperacetylated DHRS2 locus. Particularly the DHRS2 ENST00000250383.11 protein-coding isoform was increased upon HDACi treatment. Application of the HDACi quisinostat only mildly influenced the energy metabolism of urologic tumor cells, though, the analysis of the lipid metabolism showed diminished sphingosine levels, as well as decreased S1P levels. Also the ratios of S1P / sphingosine and S1P / ceramides was reduced in all four quisinostat-treated urologic tumor cells.

CONCLUSIONS

With the emphasis on urologic malignancies (testicular germ cell tumors, urothelial-, prostate-, and renal cell carcinoma), this study concluded that elevated DHRS2 levels could be indicative of a successful HDACi treatment and, thereby offering a novel putative predictive biomarker.

Informations de copyright

Copyright © 2024. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: