LncRNA SOX2OT promotes temozolomide resistance by elevating SOX2 expression via ALKBH5-mediated epigenetic regulation in glioblastoma
LncRNA SOX2OT promotes temozolomide resistance by elevating SOX2 expression via ALKBH5-mediated epigenetic regulation in glioblastoma
复制标题
LncRNA SOX2OT 通过 ALKBH5 介导的表观遗传调控提高胶质母细胞瘤中 SOX2 的表达，从而促进替莫唑胺耐药
DOI：
10.1038/s41419-020-2540-y
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发表时间：
2020-05-21
影响因子：
9
通讯作者：
Guo, Hongbo
中科院分区：
文献类型：
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作者：
Liu, Boyang;Zhou, Jian;Guo, Hongbo
替莫唑胺(TMZ)耐药是胶质母细胞瘤(GBM)复发和预后不良的主要原因。近年来，越来越多的证据表明，长非编码RNA(LncRNAs)调控着GBM的生物学过程，特别是在化疗耐药中的作用，但它们在TMZ化疗耐药中的作用尚未完全阐明。在此，我们发现LncRNA SOX2OT在TMZ耐药细胞和复发的GBM患者样本中增加，并且异常表达与复发的高风险和不良预后相关。SOX2OT基因敲除可抑制细胞增殖，促进细胞凋亡，增强TMZ敏感性。此外，我们还在体内外证实了SOX2OT通过增加SOX2的表达进而激活Wnt5a/β-catenin信号通路来调节替马西林的敏感性。机制上，进一步的研究发现SOX2OT招募了与SOX2结合的ALKBH5，使SOX2转录本去甲基化，导致SOX2表达增强。综上所述，这些结果表明，lncRNA SOX2OT通过上调SOX2的表达，激活Wnt5a/β-catenin信号通路，从而抑制细胞凋亡，促进细胞增殖，并提高对替马西林的耐药性。我们的研究结果表明，lncRNA SOX2OT可作为判断GBM预后的一种新的生物标志物，并可作为TMZ治疗的靶点。
Temozolomide (TMZ) resistance is a major cause of recurrence and poor prognosis in glioblastoma (GBM). Recently, increasing evidences suggested that long noncoding RNAs (LncRNAs) modulate GBM biological processes, especially in resistance to chemotherapy, but their role in TMZ chemoresistance has not been fully illuminated. Here, we found that LncRNA SOX2OT was increased in TMZ-resistant cells and recurrent GBM patient samples, and abnormal expression was correlated with high risk of relapse and poor prognosis. Knockdown of SOX2OT suppressed cell proliferation, facilitated cell apoptosis, and enhanced TMZ sensitivity. In addition, we identified that SOX2OT regulated TMZ sensitivity by increasing SOX2 expression and further activating the Wnt5a/β-catenin signaling pathway in vitro and in vivo. Mechanistically, further investigation revealed that SOX2OT recruited ALKBH5, which binds with SOX2, demethylating the SOX2 transcript, leading to enhanced SOX2 expression. Together, these results demonstrated that LncRNA SOX2OT inhibited cell apoptosis, promoted cell proliferation, and TMZ resistance by upregulating SOX2 expression, which activated the Wnt5a/β-catenin signaling pathway. Our findings indicate that LncRNA SOX2OT may serve as a novel biomarker for GBM prognosis and act as a therapeutic target for TMZ treatment.