RNA m(6)A reader YTHDF2 facilitates lung adenocarcinoma cell proliferation and metastasis by targeting the AXIN1/Wnt/β-catenin signaling.
RNA m(6)A reader YTHDF2 facilitates lung adenocarcinoma cell proliferation and metastasis by targeting the AXIN1/Wnt/β-catenin signaling.
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RNA m6A 阅读器 YTHDF2 通过靶向 AXIN1/Wnt/β-catenin 信号传导促进肺腺癌细胞增殖和转移
DOI：
10.1038/s41419-021-03763-z
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发表时间：
2021-05-13
影响因子：
9
通讯作者：
Xu M
中科院分区：
文献类型：
--
作者：
Li Y;Sheng H;Ma F;Wu Q;Huang J;Chen Q;Sheng L;Zhu X;Zhu X;Xu M
肺腺癌（LUAD）仍然是全球癌症相关死亡的主要原因。YTHDF 2是RNA上N6-甲基腺苷（m6 A）的阅读器，在髓性白血病的发生和传播中起着关键作用;然而，YTHDF 2是否控制LUAD的发展仍有待探索。在这里，我们发现，YTHDF 2是显着上调LUAD与癌旁正常组织相比，和YTHDF 2敲低大幅抑制，而其过表达促进，细胞生长，集落形成和迁移的LUAD细胞在体外。此外，YTHDF 2敲低显着抑制小鼠肿瘤异种移植模型中的肿瘤发生。通过对RNA-seq、m6 A-seq、CLIP-seq和RIP-seq数据集的综合分析，我们确定了LUAD中YTHDF 2的一组潜在直接靶点，其中我们确认了编码Wnt/β-catenin信号负调控因子的AXIN 1是YTHDF 2的直接靶点。YTHDF 2促进AXIN 1 mRNA降解，随后激活Wnt/β-catenin信号传导。AXIN 1的敲除充分地挽救了YTHDF 2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YTHDF 2是LUAD发展的贡献者，通过上调AXIN 1/Wnt/β-catenin信号传导起作用，这可能是LUAD的潜在治疗靶点。
Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related deaths worldwide. YTHDF2 is a reader of N6-methyladenosine (m6A) 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, m6A-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.
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