YTHDF1 Facilitates Lung Adenocarcinoma Progression via Promotion of EEF1G Translation in a m6A-Dependent Manner

Abstract

Lung adenocarcinoma (LUAD) is a malignant tumor with high morbidity and mortality worldwide, and overall survival rates for LUAD patients remain unimproved. RNA modification is a key process in post-transcriptional gene regulation in epigenetics, with N6-methyladenosine (m6A) being a common RNA modification. The molecular mechanisms of LUAD are unclear, but evidence suggests that m6A RNA methylation plays a significant role. This study aimed to clarify the role of YTHDF1 in LUAD development and pathogenesis. These findings confirmed that YTHDF1, a m6A reader protein, is highly expressed in LUAD tissues and is correlated with tumor differentiation and TNM stage. The results of functional loss experiments in LUAD cell lines revealed that downregulating YTHDF1 inhibits proliferation, migration, and invasion and induces apoptosis, with opposite effects observed upon YTHDF1 upregulation. In vivo, YTHDF1 knockout suppressed LUAD xenograft growth. RNA-seq, MeRIP-seq, RIP-seq, and bioinformatics analyses identified EEF1G as a downstream target of YTHDF1 in LUAD, and high expression of EEF1G was confirmed. The interaction between YTHDF1 and EEF1G was validated through RIP-qPCR, Co-IP and Co-IF assays. The overexpression of EEF1G in LUAD cells partially counteracts the tumor suppression induced by YTHDF1 silencing, and the knockdown of EEF1G has the opposite effect, further confirming the regulatory relationship. In summary, this study describes a novel YTHDF1/EEF1G regulatory pathway in which YTHDF1 promotes LUAD progression by recognizing and binding to the m6A-modified mRNA of EEF1G, accelerating its translation, suggesting that YTHDF1 may be a potential biomarker and therapeutic target.