Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany.
Institute of Pathology, University Medical Centre Göttingen, Göttingen, Germany.
Clin Epigenetics. 2022 Jan 7;14(1):5. doi: 10.1186/s13148-021-01223-1.
Type II germ cell tumors (GCT) are the most common solid cancers in males of age 15 to 35 years. Treatment of these tumors includes cisplatin-based therapy achieving high cure rates, but also leading to late toxicities. As mainly young men are suffering from GCTs, late toxicities play a major role regarding life expectancy, and the development of therapy resistance emphasizes the need for alternative therapeutic options. GCTs are highly susceptible to interference with the epigenetic landscape; therefore, this study focuses on screening of drugs against epigenetic factors as a treatment option for GCTs.
We present seven different epigenetic inhibitors efficiently decreasing cell viability in GCT cell lines including cisplatin-resistant subclones at low concentrations by targeting epigenetic modifiers and interactors, like histone deacetylases (Quisinostat), histone demethylases (JIB-04), histone methyltransferases (Chaetocin), epigenetic readers (MZ-1, LP99) and polycomb-repressive complexes (PRT4165, GSK343). Mass spectrometry-based analyses of the histone modification landscape revealed effects beyond the expected mode-of-action of each drug, suggesting a wider spectrum of activity than initially assumed. Moreover, we characterized the effects of each drug on the transcriptome of GCT cells by RNA sequencing and found common deregulations in gene expression of ion transporters and DNA-binding factors. A kinase array revealed deregulations of signaling pathways, like cAMP, JAK-STAT and WNT.
Our study identified seven drugs against epigenetic modifiers to treat cisplatin-resistant GCTs. Further, we extensively analyzed off-target effects and modes-of-action, which are important for risk assessment of the individual drugs.
II 型生殖细胞肿瘤（GCT）是 15 至 35 岁男性中最常见的实体肿瘤。这些肿瘤的治疗包括基于顺铂的治疗，可实现高治愈率，但也会导致晚期毒性。由于主要是年轻男性患有 GCT，因此晚期毒性对预期寿命有重大影响，而治疗耐药性的发展强调了需要替代治疗选择。GCT 极易受到表观遗传景观干扰；因此，本研究侧重于筛选针对表观遗传因子的药物作为 GCT 的治疗选择。
我们提出了七种不同的表观遗传抑制剂，通过靶向表观遗传修饰剂和相互作用子，如组蛋白去乙酰化酶（Quisinostat）、组蛋白去甲基酶（JIB-04）、组蛋白甲基转移酶（Chaetocin）、表观遗传读码器（MZ-1、LP99）和多梳抑制复合物（PRT4165、GSK343），以低浓度有效降低 GCT 细胞系包括顺铂耐药亚克隆的细胞活力。基于质谱的组蛋白修饰景观分析显示，每种药物的作用超出了预期的作用模式，表明其活性范围比最初假设的更广泛。此外，我们通过 RNA 测序分析了每种药物对 GCT 细胞转录组的影响，发现离子转运体和 DNA 结合因子的基因表达普遍失调。激酶阵列显示 cAMP、JAK-STAT 和 WNT 等信号通路的失调。
我们的研究确定了七种针对表观遗传修饰剂的药物来治疗顺铂耐药 GCT。此外，我们还广泛分析了非靶标效应和作用模式，这对于个体药物的风险评估很重要。
