N6-Methyladenosine Reader YTHDF2 Enhances Non-Small-Cell Lung Cancer Cell Proliferation and Metastasis through Mediating circ_SFMBT2 Degradation

Objective. circ_SFMBT2 was reported to facilitate malignant progression in various cancers, but its function in non-small-cell lung cancer (NSCLC) has not been fully uncovered. This study aimed to investigate the effects of N6-methyladenosine (m6A) methylation of circ_SFMBT2 (circ_0017628) on non-small-cell lung cancer (NSCLC) and its underlying mechanisms. Methods. Paired tumor and noncancerous tissues from NSCLC patients were surgically collected from January 2020 to March 2021 in our hospital. The levels of circ_SFMBT2 and LATS2 in NSCLC and human bronchial epithelial cells were assayed with qRT-PCR. Overexpression or silencing of circ_SFMBT2, LATS2, or YTHDF2 was performed in the NSCLC cells. CCK-8, colony-forming, and transwell assays were performed to analyze cell proliferation, viability, and migration, respectively. Meanwhile, the expression of MMP-9, E-cadherin, vimentin, and the Hippo/YAP pathway components was examined by western blotting. The m6A enrichment in circ_SFMBT2 was verified using methylated RNA immunoprecipitation, and interaction between circ_SFMBT2 and YTHDF2 was assessed by RNA pull-down and immunoprecipitation assays. Results. Both circ_SFMBT2 and LATS2 were lowly expressed in NSCLC cells and tissues. A positive correlation of circ_SFMBT2 with LATS2 was identified, and circ_SFMBT2 was localized predominantly in the cytoplasm. circ_SFMBT2 overexpression negatively regulated cell proliferation, viability, migration, and epithelial-mesenchymal transition while promoting the Hippo/YAP pathway activation. Notably, knockdown of LATS2 effectively abrogated the inhibitory effects of circ_SFMBT2 overexpression on NSCLC cell malignancies. Besides, m6A was specifically enriched in circ_SFMBT2, and circ_SFMBT2 could bind to YTHDF2. Silencing of YTHDF2 led to an increase in circ_SFMBT2 expression while inhibiting the malignancy of cancer cells. Conclusion. Our results showed that YTHDF2 could facilitate NSCLC cell proliferation and metastasis via the Hippo/YAP pathway activation by mediating circ_SFMBT2 degradation.