RNA m6A reader YTHDF2 facilitates lung adenocarcinoma cell proliferation and metastasis by targeting the AXIN1/Wnt/ ß-catenin signaling

Lung cancer is a leading cause of cancer-related mortality worldwide and poor prognosis remains a major problem encountered in its treatment. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has been recently implicated in the tumorigenesis and metastasis of a variety of cancers. However, the biological functions and underlying mechanisms of YTHDF2 in the regulation of lung adenocarcinoma (LUAD) progression remain elusive. Here we report that YTHDF2 expression was significantly increased in lung adenocarcinoma than in adjacent normal tissues. YTHDF2 knockdown drastically inhibited cell proliferation, colony formation, and migration in vitro, and the opposite proved true when YTHDF2 was overexpressed. In addition, YTHDF2 attenuation 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 lung adenocarcinoma. We further confirmed AXIN1, which encodes a negative regulator of the Wnt/ß-catenin signaling, as a direct target of YTHDF2. YTHDF2 promotes AXIN1 RNA decay and subsequently activates the Wnt/ß-catenin signaling. Knockout of AXIN1 can sufficiently rescue the inhibitory effect of YTHDF2 depletion on lung cancer cell proliferation, colony-formation, and migration. Collectively, our results uncovered YTHDF2-mediated regulation of the AXIN1/Wnt/ß-catenin signaling that contributes to LUAD tumorigenesis, and thus provided insight into the mechanisms underlying lung adenocarcinoma progression. Overall design: m6A profiles and mRNA profiles of control and knockdown of YTHDF2 A549 cells by deep sequencing