Abstract：
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 study, 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 expression 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 expression of specific DHRS2 isoforms, while re-analysis of ATAC-sequencing data shed light on the 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 an enhanced chromatin accessibility at the 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 were 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 are indicative of a successful HDACi treatment and, thereby offering a novel putative predictive biomarker.
METHODS: DHRS2 expression 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 expression of specific DHRS2 isoforms, while re-analysis of ATAC-sequencing data shed light on the 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 an enhanced chromatin accessibility at the 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 were 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 are indicative of a successful HDACi treatment and, thereby offering a novel putative predictive biomarker.
摘要：
背景：在肿瘤迁移过程中，入侵,克隆性,和扩散，烟酰胺腺嘌呤二核苷酸（NAD）/-磷酸（NADP）依赖性脱氢酶/还原酶成员2（DHRS2）已被认为是在抑制组蛋白脱乙酰酶（HDACi）后被诱导。在这份简短的报告中，我们评估了目前对DHRS2(epi)遗传调控的潜在机制及其在肿瘤进展过程中的功能的认识.
方法：通过qRT-PCR和蛋白质印迹分析，在用HDACi处理后，在mRNA和蛋白质水平上评估DHRS2，分别。RNA测序数据的重新分析获得了对特定DHRS2亚型的洞察，而对ATAC测序数据的重新分析使得能够分析DHRS2基因座处的染色质可及性。使用液相色谱-质谱法进一步检查HDACi处理的泌尿系统肿瘤细胞的能量和脂质代谢。
结果:在HDACi处理后增强的DHRS2表达水平与高乙酰化的DHRS2基因座直接相关。特别是DHRS2ENST00000250383.11蛋白质编码同种型在HDACi处理后增加。HDACiquisinostat的应用仅轻度影响泌尿系肿瘤细胞的能量代谢，虽然,脂质代谢分析显示鞘氨醇水平下降，以及降低S1P水平。此外，在所有四种quisinostat处理的泌尿系统肿瘤细胞中，S1P/鞘氨醇和S1P/神经酰胺的比率均降低。
结论：重点是泌尿系恶性肿瘤（睾丸生殖细胞肿瘤，尿道-，prostate-,和肾细胞癌)，这项研究得出结论，DHRS2水平升高可能表明HDACi治疗成功，从而提供了一种新的推定的预测性生物标志物。
方法：通过qRT-PCR和蛋白质印迹分析，在用HDACi处理后，在mRNA和蛋白质水平上评估DHRS2，分别。RNA测序数据的重新分析获得了对特定DHRS2亚型的洞察，而对ATAC测序数据的重新分析使得能够分析DHRS2基因座处的染色质可及性。使用液相色谱-质谱法进一步检查HDACi处理的泌尿系统肿瘤细胞的能量和脂质代谢。
结果:在HDACi处理后增强的DHRS2表达水平与高乙酰化的DHRS2基因座直接相关。特别是DHRS2ENST00000250383.11蛋白质编码同种型在HDACi处理后增加。HDACiquisinostat的应用仅轻度影响泌尿系肿瘤细胞的能量代谢，虽然,脂质代谢分析显示鞘氨醇水平下降，以及降低S1P水平。此外，在所有四种quisinostat处理的泌尿系统肿瘤细胞中，S1P/鞘氨醇和S1P/神经酰胺的比率均降低。
结论：重点是泌尿系恶性肿瘤（睾丸生殖细胞肿瘤，尿道-，prostate-,和肾细胞癌)，这项研究得出结论，DHRS2水平升高可能表明HDACi治疗成功，从而提供了一种新的推定的预测性生物标志物。
