FTO Inhibition Enhances the Antitumor Effect of Temozolomide by Targeting MYC-miR-155/23a Cluster-MXI1 Feedback Circuit in Glioma
FTO Inhibition Enhances the Antitumor Effect of Temozolomide by Targeting MYC-miR-155/23a Cluster-MXI1 Feedback Circuit in Glioma
复制标题
FTO抑制通过靶向MYC-miR-155/23a簇-MXI1反馈通路增强替莫唑胺的抗肿瘤作用
DOI：
10.1158/0008-5472.can-20-0132
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发表时间：
2020-09-15
期刊：
影响因子：
11.2
通讯作者：
Jiang, Songshan
中科院分区：
文献类型：
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作者：
Xiao, Li;Li, Xiaodi;Jiang, Songshan
恶性胶质瘤是成人致命性原发脑肿瘤之一。如此糟糕的预后需要更好地了解这种疾病的癌症相关信号通路。在这里，我们阐明了一个MYC-miRNA-MXI1反馈环，它调节胶质瘤的增殖和肿瘤发生。MYC通过microRNA-155(miR-155)和类似于27a的microRNA-23a(miR-23a簇)抑制MXI1的表达，而MXI1则通过与其启动子结合而抑制MYC的表达。MiR-155和miR-23a簇的过表达促进了U87胶质瘤细胞的成瘤。此外，脂肪质量和肥胖相关蛋白(FTO)是一种N-6-甲基腺苷(m(6)A)RNA去甲基酶，通过靶向MYC来调节环路。甲氯芬酸乙酯形式(MA2)抑制FTO，增强化疗药物替莫唑胺抑制胶质瘤细胞增殖的作用，并对环路进行负性调节。这些数据共同强调了胶质瘤中的一个关键调控回路，并为临床治疗提供了潜在的靶点。意义：这些发现阐明了一个新的反馈回路，该回路调节胶质瘤的增殖，并可以通过抑制FTO来靶向提高替莫唑胺的疗效。
Malignant glioma constitutes one of the fatal primary brain tumors in adults. Such poor prognosis calls for a better understanding of cancer-related signaling pathways of this disease. Here we elucidate a MYC-miRNA-MXI1 feedback loop that regulates proliferation and tumorigenesis in glioma. MYC suppressed MXI1 expression via microRNA-155 (miR-155) and the microRNA-23a similar to 27a similar to 24-2 cluster (miR-23a cluster), whereas MXI1, in turn, inhibited MYC expression by binding to its promoter. Overexpression of miR-155 and the miR-23a cluster promoted tumorigenesis in U87 glioma cells. Furthermore, fat mass and obesity-associated protein (FTO), an N-6-methyladenosine (m(6)A) RNA demethylase, regulated the loop by targeting MYC. The ethyl ester form of meclofenamic acid (MA2) inhibited FTO and enhanced the effect of the chemotherapy drug temozolomide on suppressing proliferation of glioma cells and negatively regulated the loop. These data collectively highlight a key regulatory circuit in glioma and provide potential targets for clinical treatment.Significance: These findings elucidate a novel feedback loop that regulates proliferation in glioma and can be targeted via inhibition of FTO to enhance the efficacy of temozolomide.