Gain-of-function mutations in the catalytic domain of DOT1L promote lung cancer malignant phenotypes via the MAPK/ERK signaling pathway
Lung cancer is a lethal malignancy lacking effective therapies. Emerging evidence suggests that epigenetic enzyme mutations are closely related to the malignant phenotype of lung cancer. Here, we identified a series of gain-of-function mutations in the histone methyltransferase DOT1L. The strongest of them is R231Q, located in the catalytic DOT domain. R231Q can enhance the substrate binding ability of DOT1L. Moreover, R231Q promotes cell growth and drug resistance of lung cancer cells in vitro and in vivo. Mechanistic studies also revealed that the R231Q mutant specifically activates the MAPK/ERK signaling pathway by enriching H3K79me2 on the RAF1 promoter and epigenetically regulating the expression of downstream targets. The combination of a DOT1L inhibitor (SGC0946) and a MAPK/ERK axis inhibitor (binimetinib) can effectively reverse the R231Q-induced phenomena. Our results reveal gain-of-function mutations in an epigenetic enzyme and provide promising insights for the precise treatment of lung cancer patients.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Science advances - 9(2023), 22 vom: 02. Juni, Seite eadc9273 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Jiayu [VerfasserIn] |
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| Links: |
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| Themen: |
DOT1L protein, human |
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| Anmerkungen: |
Date Completed 02.06.2023 Date Revised 12.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1126/sciadv.adc9273 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM357590759 |
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| 520 | |a Lung cancer is a lethal malignancy lacking effective therapies. Emerging evidence suggests that epigenetic enzyme mutations are closely related to the malignant phenotype of lung cancer. Here, we identified a series of gain-of-function mutations in the histone methyltransferase DOT1L. The strongest of them is R231Q, located in the catalytic DOT domain. R231Q can enhance the substrate binding ability of DOT1L. Moreover, R231Q promotes cell growth and drug resistance of lung cancer cells in vitro and in vivo. Mechanistic studies also revealed that the R231Q mutant specifically activates the MAPK/ERK signaling pathway by enriching H3K79me2 on the RAF1 promoter and epigenetically regulating the expression of downstream targets. The combination of a DOT1L inhibitor (SGC0946) and a MAPK/ERK axis inhibitor (binimetinib) can effectively reverse the R231Q-induced phenomena. Our results reveal gain-of-function mutations in an epigenetic enzyme and provide promising insights for the precise treatment of lung cancer patients | ||
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| 700 | 1 | |a Yang, Ting |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Mei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiaoxuan |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Weiming |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Ning |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Cui, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Shangxiao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yongshan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhai, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Lina |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jingyu |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Chunfu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Lihui |e verfasserin |4 aut | |
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