Chen Pengxiang, Li Song, Zhang Ke, Zhao Renchang, Cui Jianfeng, Zhou Wei, Liu Yuchen, Zhang Lin, Cheng Yufeng
Department of Radiation Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.
Laboratory of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.
Oncogene. 2021 Sep;40(37):5600-5612. doi: 10.1038/s41388-021-01966-4. Epub 2021 Jul 26.
N-Methyladenosine (mA) is the most prevalent epigenetic RNA modification and is vital in regulating malignancies. The roles of mA modifiers on noncoding RNAs have not been fully investigated in esophageal cancer. By screening all mA modifiers, ALKBH5 was the most potent member related to patient outcomes and suppressing esophageal cancer malignancy in cell and animal models. It demethylated pri-miR-194-2 and inhibited miR-194-2 biogenesis through an mA/DGCR8-dependent manner. RAI1, previously considered as a circadian clock transcriptional regulator, was the main target of miR-194-2. It enhanced transcription of Hippo pathway upstream genes by binding to their 3'UTR and suppressed YAP/TAZ nuclear translocation. The ALKBH5/miR-194-2/RAI1 axis was also validated in clinical samples. In addition, the increased malignancy by low ALKBH5 was abolished by the YAP inhibitor verteporfin. Our findings uncover a critical role of ALKBH5 in miRNAs biogenesis and provide novel insight for developing treatment strategies in esophageal cancer.
N-甲基腺苷（mA）是最普遍的表观遗传RNA修饰，在调节恶性肿瘤中至关重要。mA修饰因子在非编码RNA上的作用在食管癌中尚未得到充分研究。通过筛选所有mA修饰因子，ALKBH5是与患者预后相关且在细胞和动物模型中抑制食管癌恶性程度的最有效成员。它使pri-miR-194-2去甲基化，并通过一种mA/DGCR8依赖性方式抑制miR-194-2的生物合成。RAI1，先前被认为是一种生物钟转录调节因子，是miR-网络的主要靶点。它通过与Hippo通路上游基因的3'UTR结合增强其转录，并抑制YAP/TAZ核转位。ALKBH5/miR-网络/RAI1轴在临床样本中也得到了验证。此外，YAP抑制剂维替泊芬消除了低ALKBH5导致的恶性程度增加。我们的研究结果揭示了ALKBH5在miRNA生物合成中的关键作用，并为开发食管癌治疗策略提供了新的见解。
