Analysis of Dual Class I Histone Deacetylase and Lysine Demethylase Inhibitor Domatinostat (4SC-202) on Growth and Cellular and Genomic Landscape of Atypical Teratoid/Rhabdoid
Analysis of Dual Class I Histone Deacetylase and Lysine Demethylase Inhibitor Domatinostat (4SC-202) on Growth and Cellular and Genomic Landscape of Atypical Teratoid/Rhabdoid
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DOI：
10.3390/cancers12030756
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发表时间：
2020-03-01
期刊：
影响因子：
5.2
通讯作者：
Messerli, Shanta M.
中科院分区：
文献类型：
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作者：
Hoffman, Mariah M.;Zylla, Jessica S.;Messerli, Shanta M.
中枢神经系统非典型畸胎瘤样/横纹肌样瘤（ATRT）是一种罕见的侵袭性肿瘤，预后非常差。目前 ATRT 的治疗方法包括切除肿瘤，然后进行全身化疗和放射治疗，这对幼儿有毒副作用。人类 ATRT 和正常大脑样本的基因表达分析表明，ATRT 具有表观遗传标记的异常表达，包括 I 类组蛋白脱乙酰酶 (HDAC) 和赖氨酸脱甲基酶 (LSD1)。在这里，我们研究了一种名为 Domatinostat (4SC-202) 的小分子表观遗传调节剂对 ATRT 细胞存活和单细胞异质性的影响，该调节剂可抑制 I 类 HDAC 和赖氨酸脱甲基酶 (LSD1)。我们的研究结果表明，4SC-202 在 2D 和 3D 支架细胞培养模型中对 ATRT 具有细胞毒性和细胞抑制作用，并且可能靶向癌症干细胞。来自经 4SC-202 处理的 ATRT-06 球体的单细胞 RNA 测序数据显示，过度表达干细胞相关基因（包括 SOX2）的细胞数量有所减少。 3D ATRT-06 支架模型上的流式细胞术和免疫荧光支持这些结果，表明 4SC-202 降低了癌症干细胞标记物 SOX2、CD133 和 FOXM1 的表达。多组学富集分析还探讨了药物引起的系统生物学景观变化。总之，我们的数据表明，4SC-202 对 ATRT 具有细胞毒性和细胞抑制作用，针对特定细胞亚群，包括具有癌症干细胞样特征的细胞亚群，并且是一种有待体内研究的重要潜在癌症治疗剂。
Central nervous system atypical teratoid/rhabdoid tumors (ATRTs) are rare and aggressive tumors with a very poor prognosis. Current treatments for ATRT include resection of the tumor, followed by systemic chemotherapy and radiation therapy, which have toxic side effects for young children. Gene expression analyses of human ATRTs and normal brain samples indicate that ATRTs have aberrant expression of epigenetic markers including class I histone deacetylases (HDAC's) and lysine demethylase (LSD1). Here, we investigate the effect of a small molecule epigenetic modulator known as Domatinostat (4SC-202), which inhibits both class I HDAC's and Lysine Demethylase (LSD1), on ATRT cell survival and single cell heterogeneity. Our findings suggest that 4SC-202 is both cytotoxic and cytostatic to ATRT in 2D and 3D scaffold cell culture models and may target cancer stem cells. Single-cell RNA sequencing data from ATRT-06 spheroids treated with 4SC-202 have a reduced population of cells overexpressing stem cell-related genes, including SOX2. Flow cytometry and immunofluorescence on 3D ATRT-06 scaffold models support these results suggesting that 4SC-202 reduces expression of cancer stem cell markers SOX2, CD133, and FOXM1. Drug-induced changes to the systems biology landscape are also explored by multi-omics enrichment analyses. In summary, our data indicate that 4SC-202 has both cytotoxic and cytostatic effects on ATRT, targets specific cell sub-populations, including those with cancer stem-like features, and is an important potential cancer therapeutic to be investigated in vivo.