Schulte Johannes H, Lim Soyoung, Schramm Alexander, Friedrichs Nicolaus, Koster Jan, Versteeg Rogier, Ora Ingrid, Pajtler Kristian, Klein-Hitpass Ludger, Kuhfittig-Kulle Steffi, Metzger Eric, Schüle Roland, Eggert Angelika, Buettner Reinhard, Kirfel Jutta
Department of Paediatric Oncology and Hematology, University Children's Hospital Essen, Germany.
Cancer Res. 2009 Mar 1;69(5):2065-71. doi: 10.1158/0008-5472.CAN-08-1735. Epub 2009 Feb 17.
Aberrant epigenetic changes in DNA methylation and histone acetylation are hallmarks of most cancers, whereas histone methylation was previously considered to be irreversible and less versatile. Recently, several histone demethylases were identified catalyzing the removal of methyl groups from histone H3 lysine residues and thereby influencing gene expression. Neuroblastomas continue to remain a clinical challenge despite advances in multimodal therapy. Here, we address the functional significance of the chromatin-modifying enzyme lysine-specific demethylase 1 (LSD1) in neuroblastoma. LSD1 expression correlated with adverse outcome and was inversely correlated with differentiation in neuroblastic tumors. Differentiation of neuroblastoma cells resulted in down-regulation of LSD1. Small interfering RNA-mediated knockdown of LSD1 decreased cellular growth, induced expression of differentiation-associated genes, and increased target gene-specific H3K4 methylation. Moreover, LSD1 inhibition using monoamine oxidase inhibitors resulted in an increase of global H3K4 methylation and growth inhibition of neuroblastoma cells in vitro. Finally, targeting LSD1 reduced neuroblastoma xenograft growth in vivo. Here, we provide the first evidence that a histone demethylase, LSD1, is involved in maintaining the undifferentiated, malignant phenotype of neuroblastoma cells. We show that inhibition of LSD1 reprograms the transcriptome of neuroblastoma cells and inhibits neuroblastoma xenograft growth. Our results suggest that targeting histone demethylases may provide a novel option for cancer therapy.
DNA甲基化和组蛋白乙酰化异常的表观遗传变化是大多数癌症的标志，而组蛋白甲基化以前被认为是不可逆的且功能较单一。最近，几种组蛋白去甲基化酶被鉴定出来，它们催化从组蛋白H3赖氨酸残基上去除甲基基团，从而影响基因表达。尽管多模式治疗取得了进展，但神经母细胞瘤仍然是一个临床挑战。在此，我们探讨染色质修饰酶赖氨酸特异性去甲基化酶1（LSD1）在神经母细胞瘤中的功能意义。LSD1的表达与不良预后相关，且与成神经细胞瘤的分化呈负相关。神经母细胞瘤细胞的分化导致LSD1表达下调。小干扰RNA介导的LSD1敲低降低了细胞生长，诱导了分化相关基因的表达，并增加了靶基因特异性H3K4甲基化。此外，使用单胺氧化酶抑制剂抑制LSD1导致整体H3K4甲基化增加，并在体外抑制神经母细胞瘤细胞的生长。最后，靶向LSD1可降低神经母细胞瘤异种移植瘤在体内的生长。在此，我们提供了首个证据，证明组蛋白去甲基化酶LSD1参与维持神经母细胞瘤细胞未分化的恶性表型。我们表明，抑制LSD1可重编程神经母细胞瘤细胞的转录组并抑制神经母细胞瘤异种移植瘤的生长。我们的结果表明，靶向组蛋白去甲基化酶可能为癌症治疗提供一种新的选择。
