组蛋白去乙酰化酶是重要的表观遗传调节因子，已被报道在癌症干细胞功能中起着重要作用，并且在包括胶质母细胞瘤在内的许多癌症中被认为是有希望的治疗靶点。然而，具体组蛋白去乙酰化酶在胶质母细胞瘤中脑肿瘤干细胞（BTSC）亚群种保持关键自我更新和生长特征方面的功能相关角色尚未完全解析。在本研究中，我们使用药物抑制和基因失活与增活的方法，鉴定了HDAC2作为能重组染色质可及性保持BTSC生长和自我更新特性的最相关组蛋白去乙酰化酶。此外，它与转化生长因子-β通路相关蛋白SMAD3和SKI的特定相互作用对于维持体外和正位移异种移植模型中BTSC的肿瘤形成潜力至关重要。抑制HDAC2活性和破坏由HDAC2-SMAD3-SKI轴调控的协调机制因此是有希望用于靶向BTSC的治疗方法。 © 2023. Springer Nature Limited.

Histone deacetylases are important epigenetic regulators that have been reported to play essential roles in cancer stem cell functions and are promising therapeutic targets in many cancers including glioblastoma. However, the functionally relevant roles of specific histone deacetylases, in the maintenance of key self-renewal and growth characteristics of brain tumour stem cell (BTSC) sub-populations of glioblastoma, remain to be fully resolved. Here, using pharmacological inhibition and genetic loss and gain of function approaches, we identify HDAC2 as the most relevant histone deacetylase for re-organization of chromatin accessibility resulting in maintenance of BTSC growth and self-renewal properties. Furthermore, its specific interaction with the transforming growth factor-β pathway related proteins, SMAD3 and SKI, is crucial for the maintenance of tumorigenic potential in BTSCs in vitro and in orthotopic xenograft models. Inhibition of HDAC2 activity and disruption of the coordinated mechanisms regulated by the HDAC2-SMAD3-SKI axis are thus promising therapeutic approaches for targeting BTSCs.© 2023. Springer Nature Limited.