lncRNA LINC01057 promotes mesenchymal differentiation by activating NF-κB signaling in glioblastoma
lncRNA LINC01057 promotes mesenchymal differentiation by activating NF-κB signaling in glioblastoma
复制标题
lncRNA LINC01057 通过激活胶质母细胞瘤中的 NF-κ B 信号促进间充质分化
DOI：
10.1016/j.canlet.2020.10.047
复制
发表时间：
2021-02-01
期刊：
影响因子：
9.7
通讯作者：
Zheng, Guopei
中科院分区：
文献类型：
--
作者：
Tang, Guodong;Luo, Liyun;Zheng, Guopei
长链非编码RNA（longnoncodingRNAs，lncRNA）已被认为是肿瘤诊断、预后和治疗的新靶点。胶质母细胞瘤（GBM）中间充质（MES）表型的获得导致治疗抗性和不良临床结局。lncRNA和MES分化之间的相关性仍然难以捉摸。在这里，我们报告LINC01057作为lncRNA在GBM中过表达，特别是在MES亚型中。LINC01057敲低抑制体外GBM细胞的增殖、侵袭和辐射抗性，以及体内肿瘤生长。LINC01057敲低导致GBM细胞的MES亚群中MES特征的丢失，但LINC01057过表达促进前神经（PN）亚群中的MES分化。LINC01057与IKK α相互作用并维持IKK α核定位，导致通过组蛋白修饰和最终NF-κ B活化在NF-κ B应答启动子处的有效染色质可及性。IKK α敲低破坏了LINC01057过表达对PN向MES转变（PMT）的影响。LINC01057水平与MES亚型GBM患者的预后呈负相关。总的来说，我们的研究结果揭示了LINC01057作为NF-κ B信号传导的调节剂，以促进MES分化和MES亚型GBM治疗干预的潜在靶点。
Long non-coding RNAs (lncRNAs) have been potentially identified as new diagnostic markers, prognostic factors and therapeutic targets in cancer. The acquisition of a mesenchymal (MES) phenotype in glioblastomas (GBMs) results into therapeutic resistance and poor clinical outcomes. The correlation between lncRNAs and MES differentiation remains elusive. Here, we report that LINC01057 as a lncRNA is overexpressed in GBMs, especially in MES subtype. LINC01057 knockdown suppresses proliferation, invasion and radioresistance of GBM cells in vitro, and tumor growth in vivo. LINC01057 knockdown leads to loss of MES signature in MES subpopulation of GBM cells, but LINC01057 overexpression promotes MES differentiation in proneural (PN) subpopulation. LINC01057 interacts with IKK alpha and maintains IKK alpha nucleus localization, leading to effective chromatin accessibility at NF-kappa B responsive promoters via histone modification and final NF-kappa B activation. IKK alpha knockdown disrupts the effect of LINC01057 overexpression on PN to MES transition (PMT). LINC01057 level is negatively correlated with patient prognosis in MES-subtype GBM. Collectively, our findings uncover LINC01057 as a regulator of NF-kappa B signaling to promote MES differentiation and a potential target for therapeutic intervention for MES-subtype GBM.