Laboratory of Molecular Neurobiology, Neurobiology Center, The Nencki Institute of Experimental Biology, 3 Pasteur Str, 02-093, Warsaw, Poland.
Laboratory of Molecular Oncology, Military Institute of Medicine, 128 Szaserow Str, 04-141, Warsaw, Poland.
Clin Epigenetics. 2019 Jan 17;11(1):11. doi: 10.1186/s13148-018-0598-5.
The diagnosis of glioblastoma (GBM), a most aggressive primary brain tumor with a median survival of 14.6 months, carries a dismal prognosis. GBMs are characterized by numerous genetic and epigenetic alterations, affecting patient survival and treatment response. Epigenetic mechanisms are deregulated in GBM as a result of aberrant expression/activity of epigenetic enzymes, including histone deacetylases (HDAC) which remove acetyl groups from histones regulating chromatin accessibility. Nevertheless, the impact of class/isoform-selective HDAC inhibitors (HDACi) on glioma cells, including glioma stem cells, had not been systematically determined.
Comprehensive analysis of the public TCGA dataset revealed the increased expression of HDAC 1, 2, 3, and 7 in malignant gliomas. Knockdown of HDAC 1 and 2 in human GBM cells significantly decreased cell proliferation. We tested the activity of 2 new and 3 previously described HDACi with different class/isoform selectivity on human GBM cells. All tested compounds exerted antiproliferative properties on glioma cells. However, the HDACi 1 and 4 blocked proliferation of glioblastoma cells leading to G2/M growth arrest without affecting astrocyte survival. Moreover, 1 and 4 at low micromolar concentrations displayed cytotoxic and antiproliferative effects on sphere cultures enriched in glioma stem cells.
We identified two selective HDAC inhibitors that blocked proliferation of glioblastoma cells, but did not affect astrocyte survival. These new and highly effective inhibitors should be considered as promising candidates for further investigation in preclinical GBM models.
胶质母细胞瘤（GBM）是一种最具侵袭性的原发性脑肿瘤，中位生存期为 14.6 个月，预后极差。GBM 的特征是存在大量的遗传和表观遗传改变，这些改变影响患者的生存和治疗反应。表观遗传机制在 GBM 中失调，是由于表观遗传酶的异常表达/活性，包括从组蛋白上去除乙酰基的组蛋白去乙酰化酶（HDAC），从而调节染色质的可及性。然而，类/亚型选择性 HDAC 抑制剂（HDACi）对包括神经胶质瘤干细胞在内的神经胶质瘤细胞的影响尚未得到系统的确定。
对公共 TCGA 数据集的综合分析显示，恶性胶质瘤中 HDAC1、2、3 和 7 的表达增加。人 GBM 细胞中 HDAC1 和 2 的敲低显著降低了细胞增殖。我们测试了 2 种新的和 3 种以前描述的具有不同类/亚型选择性的 HDACi 对人 GBM 细胞的活性。所有测试的化合物对神经胶质瘤细胞均具有抗增殖作用。然而，HDACi1 和 4 阻断了神经胶质瘤细胞的增殖，导致 G2/M 期生长停滞，而不影响星形胶质细胞的存活。此外，1 和 4 在低微摩尔浓度下对富含神经胶质瘤干细胞的球体培养物显示出细胞毒性和抗增殖作用。
我们鉴定了两种选择性 HDAC 抑制剂，它们可以阻断神经胶质瘤细胞的增殖，但不影响星形胶质细胞的存活。这些新的和高效的抑制剂应被视为在临床前 GBM 模型中进一步研究的有前途的候选物。
