胶质母细胞瘤是成人最常见的原发性恶性脑肿瘤，中位生存期仅超过 1 年。现有治疗方法未能使胶质母细胞瘤 (GBM) 患者获得缓解，原因是癌症干细胞 (CSC) 的存在，人们认为这些细胞在肿瘤的发生和进展中发挥着核心作用，并且是一种耐药细胞能够驱动肿瘤复发的储存库。事实上，“干性”本身的特性可能是造成治疗抵抗的原因。在这项研究中，我们发现了一种新型长非编码RNA (lncRNA)，即癌症干细胞相关的SOX2远端增强子(CASCADES)，它在神经胶质瘤CSC (GSC)中充当表观遗传调节因子。 CASCADE 在异柠檬酸脱氢酶 (IDH) 野生型 GBM 中表达，并且在 GSC 中显着富集。 GSC 中 CASCADE 的敲低会导致以细胞和癌症特异性方式分化为神经元谱系。生物信息学分析表明，CASCADES 是 SOX2 的超级增强子相关 lncRNA 表观遗传调节因子。我们的研究结果表明，CASCADES 是 GSC 干性的关键调节因子，代表了破坏胶质母细胞瘤中 CSC 区室的新型表观遗传学和治疗靶点。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Glioblastoma is the most common primary malignant brain tumor in adults, with a median survival of just over 1 year. The failure of available treatments to achieve remission in patients with glioblastoma (GBM) has been attributed to the presence of cancer stem cells (CSCs), which are thought to play a central role in tumor development and progression and serve as a treatment-resistant cell repository capable of driving tumor recurrence. In fact, the property of "stemness" itself may be responsible for treatment resistance. In this study, we identify a novel long noncoding RNA (lncRNA), cancer stem cell-associated distal enhancer of SOX2 (CASCADES), that functions as an epigenetic regulator in glioma CSCs (GSCs). CASCADES is expressed in isocitrate dehydrogenase (IDH)-wild-type GBM and is significantly enriched in GSCs. Knockdown of CASCADES in GSCs results in differentiation towards a neuronal lineage in a cell- and cancer-specific manner. Bioinformatics analysis reveals that CASCADES functions as a super-enhancer-associated lncRNA epigenetic regulator of SOX2. Our findings identify CASCADES as a critical regulator of stemness in GSCs that represents a novel epigenetic and therapeutic target for disrupting the CSC compartment in glioblastoma.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.