Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.
Cancer Lett. 2024 Nov 1;604:217269. doi: 10.1016/j.canlet.2024.217269. Epub 2024 Sep 24.
Glioblastoma (GBM) is a fatal adult brain tumor with an extremely poor prognosis. GBM poses significant challenges for targeted therapies due to its intra- and inter-tumoral heterogeneity, a highly immunosuppressive microenvironment, diffuse infiltration into normal brain parenchyma, protection by the blood-brain barrier and acquisition of therapeutic resistance. Recent studies have implicated epigenetic modifiers as key players driving tumorigenesis, resistance, and progression of GBM. While the vast majority of GBM research on epigenetic modifiers thus far has focused predominantly on elucidating the functional roles and targeting of DNA methyltransferases and histone deacetylases, emerging evidence indicates that histone acetyltransferases (HATs) also play a key role in mediating plasticity and therapeutic resistance in GBM. Here, we will provide an overview of HATs, their dual roles and functions in cancer as both tumor suppressors and oncogenes and focus specifically on their implications in GBM resistance. We also discuss the technical challenges in developing selective HAT inhibitors and highlight their promise as potential anti-cancer therapeutics for treating intractable cancers such as GBM.
胶质母细胞瘤（GBM）是一种致命的成人脑肿瘤，预后极差。由于其内在和肿瘤间的异质性、高度免疫抑制的微环境、弥漫性浸润正常脑实质、血脑屏障的保护以及获得治疗耐药性，GBM 对靶向治疗构成了重大挑战。最近的研究表明，表观遗传修饰剂是驱动 GBM 发生、耐药和进展的关键因素。虽然迄今为止，绝大多数关于表观遗传修饰剂的 GBM 研究主要集中在阐明 DNA 甲基转移酶和组蛋白去乙酰化酶的功能作用和靶向作用，但新出现的证据表明，组蛋白乙酰转移酶（HATs）在介导 GBM 的可塑性和治疗耐药性方面也发挥着关键作用。在这里，我们将概述 HATs 及其在癌症中的双重作用和功能，作为肿瘤抑制因子和癌基因，并特别关注它们在 GBM 耐药性中的意义。我们还讨论了开发选择性 HAT 抑制剂的技术挑战，并强调了它们作为治疗难治性癌症（如 GBM）的潜在抗癌治疗药物的前景。
