Zhang Sicong, Zhao Boxuan Simen, Zhou Aidong, Lin Kangyu, Zheng Shaoping, Lu Zhike, Chen Yaohui, Sulman Erik P, Xie Keping, Bögler Oliver, Majumder Sadhan, He Chuan, Huang Suyun
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Program in Cancer Biology, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
Cancer Cell. 2017 Apr 10;31(4):591-606.e6. doi: 10.1016/j.ccell.2017.02.013. Epub 2017 Mar 23.
The dynamic and reversible N-methyladenosine (mA) RNA modification installed and erased by N-methyltransferases and demethylases regulates gene expression and cell fate. We show that the mA demethylase ALKBH5 is highly expressed in glioblastoma stem-like cells (GSCs). Silencing ALKBH5 suppresses the proliferation of patient-derived GSCs. Integrated transcriptome and mA-seq analyses revealed altered expression of certain ALKBH5 target genes, including the transcription factor FOXM1. ALKBH5 demethylates FOXM1 nascent transcripts, leading to enhanced FOXM1 expression. Furthermore, a long non-coding RNA antisense to FOXM1 (FOXM1-AS) promotes the interaction of ALKBH5 with FOXM1 nascent transcripts. Depleting ALKBH5 and FOXM1-AS disrupted GSC tumorigenesis through the FOXM1 axis. Our work uncovers a critical function for ALKBH5 and provides insight into critical roles of mA methylation in glioblastoma.
由N-甲基转移酶和去甲基酶安装和去除的动态可逆N-甲基腺苷（mA）RNA修饰调节基因表达和细胞命运。我们发现mA去甲基酶ALKBH5在胶质母细胞瘤干细胞样细胞（GSCs）中高度表达。沉默ALKBH5可抑制患者来源的GSCs的增殖。综合转录组和mA-seq分析揭示了某些ALKBH5靶基因的表达改变，包括转录因子FOXM1。ALKBH5使FOXM1新生转录本去甲基化，导致FOXM1表达增强。此外，一种与FOXM1反义的长链非编码RNA（FOXM1-AS）促进ALKBH5与FOXM1新生转录本的相互作用。通过FOXM1轴耗尽ALKBH5和FOXM1-AS破坏了GSC的肿瘤发生。我们的工作揭示了ALKBH5的关键功能，并为mA甲基化在胶质母细胞瘤中的关键作用提供了见解。
