Ythdf1 promotes cyclin b1 translation through m6 a modulation and contributes to the poor prognosis of lung adenocarcinoma with kras/tp53 co‐mutation

Abstract

KRAS and TP53 mutations are the two most common driver mutations in patients with lung adenocarcinoma (LUAD), and they appear to reduce latency and increase metastatic proclivity when a KRAS and TP53 co‐mutation (KRAS/TP53‐mut) occurs. However, the molecular mechanism involved is unclear. N6‐methyladenosine (m6A), the most abundant RNA modification in mammal mRNAs, plays a critical role in tumorigenesis. Here, we used genomic and transcriptomic data and found that only LUAD patients with KRAS/TP53‐mut, but not an individual mutation, appeared to exhibit poor overall survival when compared with patients without KRAS and TP53 mutation (wildtype). Subsequently, we analyzed the differential expression of the 15‐m6A‐related genes in LUAD with different mutations and found that YTHDF1 was the most upregulated in KRAS/TP53‐ mut patients and associated with their adverse prognosis. Bioinformatics and experimental evidence indicated that elevated YTHDF1 functionally promoted the translation of cyclin B1 mRNA in an m6 A‐dependent manner, thereby facilitating the tumor proliferation and poor prognosis of LUAD with KRAS/TP53‐mut. Furthermore, the concurrent increase in YTHDF1 and cyclin B1 was confirmed by immunohistochemistry staining in patients with co‐occurring KRAS/TP53 mutations. YTHDF1 was correlated with an unfavorable clinical stage and tumor size. Collectively, we identi-fied and confirmed a novel “YTHDF1–m6A–cyclin B1 translation” axis as an essential molecular pathway for the prognosis of KRAS/TP53‐mut LUAD.