Deciphering the molecular effects of romidepsin on germ cell tumours: DHRS2 is involved in cell cycle arrest but not apoptosis or induction of romidepsin effectors

In this study, we extended our analysis of the molecular effects of romidepsin to deepen our understanding of the underlying mechanisms. P atients will benefit from these analyses, since detailed knowledge of the romidepsin effects allows for a better risk and side‐effect assessment. We screened for changes in histone acetylation of specific lysine residues and analysed changes in the DNA methylation landscape after romidepsin treatm ent of the GCT cell lines TCam‐2, 2102EP, NCCIT and JAR, while human fibroblasts were used as controls. In addition, we focused on the role of the dehydrogenase/reductaseDHRS2, which was strongly up ‐regulated in romidepsin treated cells, by generatingDHRS2‐deficient TCam‐2 cells using CRISPR/Cas9 gene editing. We show that DHRS2 is dispensable for up‐regulation of romidepsin effectors (GADD45B, DUSP1, ZFP36, ATF3, FOS, CDKN1A, ID2) but contributes to induction of cell cycle arrest. Finally, we show that a combinatory treatment of romidepsin plus the gluccocorticoid dexamethasone further boosts expression of the romidepsin effectors and reduces viability of GCT cells more strongly than under single agent treatment. Thus, romidepsin and dexamethasone might represent a new combinatorial approach for treatment of GCT.
Source: Journal of Cellular and Molecular Medicine - Category: Molecular Biology Authors: Tags: ORIGINAL ARTICLE Source Type: research