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Cells
Volume 10
Issue 7
10.3390/cells10071669
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Article

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

by
Xiaoying Lou
1,†,
Jinfeng Ning
2,†,
Wei Liu
3,†,
Kexin Li
1,
Benheng Qian
4,
Danfei Xu
1,
Yue Wu
1,
Donghong Zhang
5,* and
Wei Cui
1,*
1
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
2
The Thoracic Department of Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin 150040, China
3
The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin 150040, China
4
Department of Cardiology, The Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Road, Wenzhou 325027, China
5
Center for Molecular and Translational Medicine, Research Science Center, Georgia State University, Atlanta, GA 30303, USA
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally.
Cells 2021, 10(7), 1669; https://doi.org/10.3390/cells10071669
Submission received: 26 April 2021 / Revised: 28 June 2021 / Accepted: 28 June 2021 / Published: 2 July 2021
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Lung Cancers)
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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.
Keywords: lung adenocarcinoma; KRAS/TP53 mutation; YTHDF1; cyclin B1; m6A modification lung adenocarcinoma; KRAS/TP53 mutation; YTHDF1; cyclin B1; m6A modification

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MDPI and ACS Style

Lou, X.; Ning, J.; Liu, W.; Li, K.; Qian, B.; Xu, D.; Wu, Y.; Zhang, D.; Cui, W. YTHDF1 Promotes Cyclin B1 Translation through m6A Modulation and Contributes to the Poor Prognosis of Lung Adenocarcinoma with KRAS/TP53 Co-Mutation. Cells 2021, 10, 1669. https://doi.org/10.3390/cells10071669

AMA Style

Lou X, Ning J, Liu W, Li K, Qian B, Xu D, Wu Y, Zhang D, Cui W. YTHDF1 Promotes Cyclin B1 Translation through m6A Modulation and Contributes to the Poor Prognosis of Lung Adenocarcinoma with KRAS/TP53 Co-Mutation. Cells. 2021; 10(7):1669. https://doi.org/10.3390/cells10071669

Chicago/Turabian Style

Lou, Xiaoying, Jinfeng Ning, Wei Liu, Kexin Li, Benheng Qian, Danfei Xu, Yue Wu, Donghong Zhang, and Wei Cui. 2021. "YTHDF1 Promotes Cyclin B1 Translation through m6A Modulation and Contributes to the Poor Prognosis of Lung Adenocarcinoma with KRAS/TP53 Co-Mutation" Cells 10, no. 7: 1669. https://doi.org/10.3390/cells10071669

APA Style

Lou, X., Ning, J., Liu, W., Li, K., Qian, B., Xu, D., Wu, Y., Zhang, D., & Cui, W. (2021). YTHDF1 Promotes Cyclin B1 Translation through m6A Modulation and Contributes to the Poor Prognosis of Lung Adenocarcinoma with KRAS/TP53 Co-Mutation. Cells, 10(7), 1669. https://doi.org/10.3390/cells10071669

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