Ivy Brain Tumor Center, Barrow Neurological Institute, Phoenix, Arizona, USA.
Interdisciplinary Graduate Program in Neuroscience, School of Life Sciences, and.
JCI Insight. 2021 Sep 8;6(17):e149232. doi: 10.1172/jci.insight.149232.
Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. One major family of epigenetic regulators, the histone deacetylases (HDACs), are considered promising therapeutic targets for GBM due to their repressive influences on transcription. Although HDACs share redundant functions and common substrates, the unique isoform-specific roles of different HDACs in GBM remain unclear. In neural stem cells, HDAC2 is the indispensable deacetylase to ensure normal brain development and survival in the absence of HDAC1. Surprisingly, we find that HDAC1 is the essential class I deacetylase in glioma stem cells, and its loss is not compensated for by HDAC2. Using cell-based and biochemical assays, transcriptomic analyses, and patient-derived xenograft models, we find that knockdown of HDAC1 alone has profound effects on the glioma stem cell phenotype in a p53-dependent manner. We demonstrate marked suppression in tumor growth upon targeting of HDAC1 and identify compensatory pathways that provide insights into combination therapies for GBM. Our study highlights the importance of HDAC1 in GBM and the need to develop isoform-specific drugs.
胶质母细胞瘤（GBM）的特征是存在异常但可药物治疗的表观遗传景观。表观遗传调节剂的一个主要家族，组蛋白去乙酰化酶（HDACs），由于它们对转录的抑制作用，被认为是 GBM 有前途的治疗靶点。尽管 HDACs 具有冗余的功能和共同的底物，但不同 HDAC 在 GBM 中的独特同工型特异性作用尚不清楚。在神经干细胞中，HDAC2 是确保正常大脑发育和在没有 HDAC1 的情况下存活所必需的去乙酰化酶。令人惊讶的是，我们发现 HDAC1 是神经胶质瘤干细胞中必不可少的 I 类去乙酰化酶，其缺失不能被 HDAC2 代偿。通过细胞和生化测定、转录组分析和患者来源的异种移植模型，我们发现单独敲低 HDAC1 以依赖于 p53 的方式对神经胶质瘤干细胞表型产生深远影响。我们证明了针对 HDAC1 的靶向治疗对肿瘤生长有明显的抑制作用，并确定了补偿途径，为 GBM 的联合治疗提供了思路。我们的研究强调了 HDAC1 在 GBM 中的重要性，以及开发同工型特异性药物的必要性。
