DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferation
Summary: Histone lysine methylation functions at the interface of the extracellular environment and intracellular gene expression. DOT1L is a versatile histone H3K79 methyltransferase with a prominent role in MLL-fusion leukemia, yet little is known about how DOT1L responds to extracellular stimuli....
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-09-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472101192X |
| _version_ | 1818647300205969408 |
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| author | Tanjing Song Qingli Zou Yingying Yan Suli Lv Neng Li Xuefeng Zhao Xianyun Ma Haigang Liu Borui Tang Lidong Sun |
| author_facet | Tanjing Song Qingli Zou Yingying Yan Suli Lv Neng Li Xuefeng Zhao Xianyun Ma Haigang Liu Borui Tang Lidong Sun |
| author_sort | Tanjing Song |
| collection | DOAJ |
| description | Summary: Histone lysine methylation functions at the interface of the extracellular environment and intracellular gene expression. DOT1L is a versatile histone H3K79 methyltransferase with a prominent role in MLL-fusion leukemia, yet little is known about how DOT1L responds to extracellular stimuli. Here, we report that DOT1L protein stability is regulated by the extracellular glucose level through the hexosamine biosynthetic pathway (HBP). Mechanistically, DOT1L is O-GlcNAcylated at evolutionarily conserved S1511 in its C terminus. We identify UBE3C as a DOT1L E3 ubiquitin ligase promoting DOT1L degradation whose interaction with DOT1L is susceptible to O-GlcNAcylation. Consequently, HBP enhances H3K79 methylation and expression of critical DOT1L target genes such as HOXA9/MEIS1, promoting cell proliferation in MLL-fusion leukemia. Inhibiting HBP or O-GlcNAc transferase (OGT) increases cellular sensitivity to DOT1L inhibitor. Overall, our work uncovers O-GlcNAcylation and UBE3C as critical determinants of DOT1L protein abundance, revealing a mechanism by which glucose metabolism affects malignancy progression through histone methylation. |
| first_indexed | 2024-12-17T01:00:20Z |
| format | Article |
| id | doaj.art-0054597c9b3140178d3791e6422b846e |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-17T01:00:20Z |
| publishDate | 2021-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-0054597c9b3140178d3791e6422b846e2022-12-21T22:09:29ZengElsevierCell Reports2211-12472021-09-013612109739DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferationTanjing Song0Qingli Zou1Yingying Yan2Suli Lv3Neng Li4Xuefeng Zhao5Xianyun Ma6Haigang Liu7Borui Tang8Lidong Sun9Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China; Corresponding authorDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China; Corresponding authorSummary: Histone lysine methylation functions at the interface of the extracellular environment and intracellular gene expression. DOT1L is a versatile histone H3K79 methyltransferase with a prominent role in MLL-fusion leukemia, yet little is known about how DOT1L responds to extracellular stimuli. Here, we report that DOT1L protein stability is regulated by the extracellular glucose level through the hexosamine biosynthetic pathway (HBP). Mechanistically, DOT1L is O-GlcNAcylated at evolutionarily conserved S1511 in its C terminus. We identify UBE3C as a DOT1L E3 ubiquitin ligase promoting DOT1L degradation whose interaction with DOT1L is susceptible to O-GlcNAcylation. Consequently, HBP enhances H3K79 methylation and expression of critical DOT1L target genes such as HOXA9/MEIS1, promoting cell proliferation in MLL-fusion leukemia. Inhibiting HBP or O-GlcNAc transferase (OGT) increases cellular sensitivity to DOT1L inhibitor. Overall, our work uncovers O-GlcNAcylation and UBE3C as critical determinants of DOT1L protein abundance, revealing a mechanism by which glucose metabolism affects malignancy progression through histone methylation.http://www.sciencedirect.com/science/article/pii/S221112472101192XO-GlcNAcylationDOT1LhistonemethylationglucoseMLL |
| spellingShingle | Tanjing Song Qingli Zou Yingying Yan Suli Lv Neng Li Xuefeng Zhao Xianyun Ma Haigang Liu Borui Tang Lidong Sun DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferation Cell Reports O-GlcNAcylation DOT1L histone methylation glucose MLL |
| title | DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferation |
| title_full | DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferation |
| title_fullStr | DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferation |
| title_full_unstemmed | DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferation |
| title_short | DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferation |
| title_sort | dot1l o glcnacylation promotes its protein stability and mll fusion leukemia cell proliferation |
| topic | O-GlcNAcylation DOT1L histone methylation glucose MLL |
| url | http://www.sciencedirect.com/science/article/pii/S221112472101192X |
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