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

Cells

Donghong Zhang¹  Benheng Qian²  Xiaoying Lou³  Kexin Li³  Danfei Xu³  Yue Wu³  Wei Cui³  Wei Liu⁴  Jinfeng Ning⁵ 

[1] Center for Molecular and Translational Medicine, Research Science Center, Georgia State University, Atlanta, GA 30303, USA;Department of Cardiology, The Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Road, Wenzhou 325027, China;National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, State Key Laboratory of Molecular Oncology, Department of Clinical Laboratory, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China;The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin 150040, China;The Thoracic Department of Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin 150040, China;

关键词: lung adenocarcinoma;    KRAS/TP53 mutation;    YTHDF1;    cyclin B1;    m⁶A modification;   

DOI  :  10.3390/cells10071669

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown