YTHDF1 Promotes Cyclin B1 Translation through m6A Modulation and Contributes to the Poor Prognosis of Lung Adenocarcinoma with KRAS/TP53 Co-Mutation.

Xiaoying Lou,Benheng Qian,Wei Cui,Yue Wu,Danfei Xu,Kexin Li,Jinfeng Ning,Wei Liu,Donghong Zhang

doi:10.3390/cells10071669

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 m6A-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 identified and confirmed a novel “YTHDF1–m6A–cyclin B1 translation” axis as an essential molecular pathway for the prognosis of KRAS/TP53-mut LUAD.

Highlights

Increased YTHDF1 Expression Is Associated with a Poor Prognosis in lung adenocarcinoma (LUAD) Patients with
(b) Heatmap of mRNA expression of the m6 A-related genes in the wildtype (n = 108), KRAS-mut (n = 66), TP53-mut (n = 147), and KRAS/TP53-mut (n = 44) groups of the LUAD cohort. (c) Plot showing the mRNA expression of YTHDF1 in four different mutation groups. (d) Kaplan–Meier survival plots for male LUAD patients stratified by quantile (0.25 and 0.75)
Our results indicated that YTHDF1 is associated with the translation efficiency of cyclin B1, which promotes cell proliferation in co-mutant KRAS/TP53 lung cancer

Summary

Introduction

Patients driven by the oncogenic alteration of KRAS can vary considerably in their histological appearance and immunohistochemical profile [2]. Mutations in tumor suppressor genes TP53 and STK11 are common in LUAD and frequently co-occur with the KRAS mutation [3,4,5]. Recent studies have demonstrated that the co-occurrence of TP53 and STK11 has a profound influence on the molecular and clinical heterogeneity of KRAS-driven lung cancers. An oncogenic KRAS-mutant with p53 loss can induce LUAD with reduced latency and increased metastatic proclivity [6]. This raises the question of whether co-mutations impact the prognosis of LUAD

Methods

Results

Conclusion