YTHDF1 Promotes Cyclin B1 Translation through m6A Modulation and Contributes to the Poor Prognosis of Lung Adenocarcinoma with KRAS/TP53 Co-Mutation
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Cells - 10(2021), 7 vom: 02. Juli |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lou, Xiaoying [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.10.2021 Date Revised 26.10.2021 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/cells10071669 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM329041029 |
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| 100 | 1 | |a Lou, Xiaoying |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a YTHDF1 Promotes Cyclin B1 Translation through m6A Modulation and Contributes to the Poor Prognosis of Lung Adenocarcinoma with KRAS/TP53 Co-Mutation |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 26.10.2021 | ||
| 500 | |a Date Revised 26.10.2021 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a KRAS/TP53 mutation | |
| 650 | 4 | |a YTHDF1 | |
| 650 | 4 | |a cyclin B1 | |
| 650 | 4 | |a lung adenocarcinoma | |
| 650 | 4 | |a m6A modification | |
| 650 | 7 | |a CCNB1 protein, human |2 NLM | |
| 650 | 7 | |a Cyclin B1 |2 NLM | |
| 650 | 7 | |a KRAS protein, human |2 NLM | |
| 650 | 7 | |a RNA, Messenger |2 NLM | |
| 650 | 7 | |a RNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a TP53 protein, human |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 650 | 7 | |a YTHDF1 protein, human |2 NLM | |
| 650 | 7 | |a N-methyladenosine |2 NLM | |
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| 650 | 7 | |a Proto-Oncogene Proteins p21(ras) |2 NLM | |
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| 650 | 7 | |a Adenosine |2 NLM | |
| 650 | 7 | |a K72T3FS567 |2 NLM | |
| 700 | 1 | |a Ning, Jinfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Kexin |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Benheng |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Danfei |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Donghong |e verfasserin |4 aut | |
| 700 | 1 | |a Cui, Wei |e verfasserin |4 aut | |
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