低级别和次高级别胶质瘤中常含有IDH1或IDH2代谢酶的突变，据推测这些突变通过抑制许多调节DNA结构的染色质调节酶从而推动肿瘤发生。组蛋白去乙酰化酶抑制剂是有希望的抗癌剂，并已在临床试验中使用。然而，对其机制或基因靶点的清晰理解尚不足够。在这项研究中，作者通过遗传学手段对患者源性IDH1突变细胞进行分析，以确定哪些组蛋白去乙酰化酶推动IDH1突变胶质瘤的生长。对一系列患者源性胶质瘤干细胞系（2个IDH1突变系，3个IDH1野生型系）进行了来自不同表观遗传类别的表观遗传修饰药物的药物筛选。测试了LBH（泛博多妥）对患者源性IDH1突变系的基因表达和染色质结构的影响。使用患者源性IDH1突变的胶质母细胞瘤体外模型（HK252），通过慢病毒RNA干扰敲除载体，分子解剖了高表达的每个组蛋白去乙酰化酶在生长中的作用。然后，在体内异种移植模型（BT-142）中对这些结果进行了验证。IDH1突变导致两个不同IDH1突变过表达模型中的基因下调，DNA高甲基化，DNA可及性增加和H3K27低乙酰化。药物筛选确定了组蛋白去乙酰化酶抑制剂（HDACi）和泛博多妥（LBH）作为最具选择性的抑制IDH1突变胶质瘤系生长的化合物。在这十一种注释的组蛋白去乙酰化酶（HDAC1-11）中，只有六种在IDH1突变胶质瘤组织样本和患者源性胶质瘤干细胞系中表达（HDAC1-4，HDAC6和HDAC9）。慢病毒敲减实验证明HDAC1和HDAC6是最一致地对体外和体内生长至关重要并且靶向不同基因模块的酶。在体内敲减HDAC1或HDAC6导致了范围较小、侵袭性较弱的肿瘤。IDH1突变引起的基因失调是广泛的，只有部分能够通过直接抑制IDH1来逆转。本研究鉴定了HDAC1和HDAC6作为重要的可靶向酶，对IDH1突变胶质瘤的生长和侵袭性发挥重要作用。© 2023. 作者。

Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting many of the chromatin-regulating enzymes that regulate DNA structure. Histone deacetylase inhibitors are promising anti-cancer agents and have already been used in clinical trials. However, a clear understanding of their mechanism or gene targets is lacking. In this study, the authors genetically dissect patient-derived IDH1 mutant cultures to determine which HDAC enzymes drive growth in IDH1 mutant gliomas. A panel of patient-derived gliomasphere cell lines (2 IDH1 mutant lines, 3 IDH1 wildtype lines) were subjected to a drug-screen of epigenetic modifying drugs from different epigenetic classes. The effect of LBH (panobinostat) on gene expression and chromatin structure was tested on patient-derived IDH1 mutant lines. The role of each of the highly expressed HDAC enzymes was molecularly dissected using lentiviral RNA interference knock-down vectors and a patient-derived IDH1 mutant in vitro model of glioblastoma (HK252). These results were then confirmed in an in vivo xenotransplant model (BT-142). The IDH1 mutation leads to gene down-regulation, DNA hypermethylation, increased DNA accessibility and H3K27 hypo-acetylation in two distinct IDH1 mutant over-expression models. The drug screen identified histone deacetylase inhibitors (HDACi) and panobinostat (LBH) more specifically as the most selective compounds to inhibit growth in IDH1 mutant glioma lines. Of the eleven annotated HDAC enzymes (HDAC1-11) only six are expressed in IDH1 mutant glioma tissue samples and patient-derived gliomasphere lines (HDAC1-4, HDAC6, and HDAC9). Lentiviral knock-down experiments revealed that HDAC1 and HDAC6 are the most consistently essential for growth both in vitro and in vivo and target very different gene modules. Knock-down of HDAC1 or HDAC6 in vivo led to a more circumscribed less invasive tumor. The gene dysregulation induced by the IDH1 mutation is wide-spread and only partially reversible by direct IDH1 inhibition. This study identifies HDAC1 and HDAC6 as important and drug-targetable enzymes that are necessary for growth and invasiveness in IDH1 mutant gliomas.© 2023. The Author(s).