Department of Oncology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, P. R. China.
National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, P. R. China.
Cell Death Dis. 2021 May 13;12(5):479. doi: 10.1038/s41419-021-03763-z.
Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related deaths worldwide. YTHDF2 is a reader of N-methyladenosine (mA) on RNA and plays a critical role in the initiation and propagation of myeloid leukemia; however, whether YTHDF2 controls the development of LUAD remains to be explored. Here, we found that YTHDF2 was significantly upregulated in LUAD compared with paracancerous normal tissues, and YTHDF2 knockdown drastically inhibited, while its overexpression promoted, cell growth, colony formation and migration of LUAD cells in vitro. In addition, YTHDF2 knockdown significantly inhibited tumorigenesis in a murine tumor xenograft model. Through the integrative analysis of RNA-seq, mA-seq, CLIP-seq, and RIP-seq datasets, we identified a set of potential direct targets of YTHDF2 in LUAD, among which we confirmed AXIN1, which encodes a negative regulator of the Wnt/β-catenin signaling, as a direct target of YTHDF2. YTHDF2 promoted AXIN1 mRNA decay and subsequently activated the Wnt/β-catenin signaling. Knockout of AXIN1 sufficiently rescued the inhibitory effect of YTHDF2 depletion on lung cancer cell proliferation, colony-formation, and migration. These results revealed YTHDF2 to be a contributor of LUAD development acting through the upregulation of the AXIN1/Wnt/β-catenin signaling, which can be a potential therapeutic target for LUAD.
肺腺癌（LUAD）仍然是全球癌症相关死亡的主要原因。YTHDF2 是 RNA 上 N6-甲基腺苷（m6A）的阅读器，在髓系白血病的起始和传播中起着关键作用；然而，YTHDF2 是否控制 LUAD 的发展仍有待探索。在这里，我们发现与癌旁正常组织相比，LUAD 中 YTHDF2 显著上调，YTHDF2 敲低明显抑制，而过表达则促进 LUAD 细胞的体外生长、集落形成和迁移。此外，YTHDF2 敲低显著抑制了小鼠肿瘤异种移植模型中的肿瘤发生。通过对 RNA-seq、m6A-seq、CLIP-seq 和 RIP-seq 数据集的综合分析，我们确定了 YTHDF2 在 LUAD 中的一组潜在的直接靶标，其中我们证实 AXIN1，它编码 Wnt/β-catenin 信号的负调节剂，是 YTHDF2 的直接靶标。YTHDF2 促进 AXIN1 mRNA 降解，随后激活 Wnt/β-catenin 信号。AXIN1 的敲除充分挽救了 YTHDF2 耗竭对肺癌细胞增殖、集落形成和迁移的抑制作用。这些结果表明 YTHDF2 通过上调 AXIN1/Wnt/β-catenin 信号促进 LUAD 的发展，这可能是 LUAD 的一个潜在治疗靶点。
