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Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance

文献类型：期刊论文

作者Liu, Yi1; Liang, Guanghao2,3; Xu, Hongjiao4,5; Dong, Wenxin1; Dong, Ze4,5; Qiu, Zhiwei1; Zhang, Zihao1; Li, Fangle2,3; Huang, Yue4,5,6; Li, Yilin1
刊名CELL METABOLISM
出版日期2021-06-01
卷号33期号:6页码:1221-+
ISSN号1550-4131
DOI10.1016/j.cmet.2021.04.001
通讯作者Han, Dali(handl@big.ac.cn) ; Yang, Cai-Guang(yangcg@simm.ac.cn) ; Xu, Meng Michelle(michellexu@mail.tsinghua.edu.cn)
英文摘要The ever-increasing understanding of the complexity of factors and regulatory layers that contribute to immune evasion facilitates the development of immunotherapies. However, the diversity of malignant tumors limits many known mechanisms in specific genetic and epigenetic contexts, manifesting the need to discover general driver genes, Here, we have identified the m(6)A demethylase FTO as an essential epitranscriptomic regulator utilized by tumors to escape immune surveillance through regulation of glycolytic metabolism. We show that FTO-mediated m(6)A demethylation in tumor cells elevates the transcription factors c-Jun, JunB, and C/EBP beta, which allows the rewiring of glycolytic metabolism. Fto knockdown impairs the glycolytic activity of tumor cells, which restores the function of CD8(+) T cells, thereby inhibiting tumor-growth. Furthermore, we developed a small-molecule compound, Dac51 , that can inhibit the activity of FTO, block FTO-mediated immune evasion, and synergize with checkpoint blockade for better tumor control, suggesting reprogramming RNA epitranscriptome as a potential strategy for immunotherapy.
WOS关键词DENDRITIC CELLS ; SELF-RENEWAL ; RNA ; RESISTANCE ; EXPRESSION ; DEMETHYLASE ; TARGET ; MECHANISMS ; ULTRAFAST ; CHROMATIN
资助项目Beijing Natural Science Foundation[Z200023] ; Strategic Priority Research Program[XDA16010115] ; National Natural Science Foundation of China[81922054] ; National Natural Science Foundation of China[21725801] ; National Natural Science Foundation of China[31922017] ; National Natural Science Foundation of China[91853132] ; National Natural Science Foundation of China[21807103] ; National Natural Science Foundation of China[21907101] ; National Key R&D Program of China[2016YFA0501500] ; National Key R&D Program of China[2018YFA0109700] ; Key Research Program of Frontier Sciences, Chinese Academy of Sciences[ZDBS-LY-SM013] ; CAS Hundred Talent Program ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[18YF1428500]
WOS研究方向Cell Biology ; Endocrinology & Metabolism
语种英语
WOS记录号WOS:000658751400004
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/297074]  
专题新药研究国家重点实验室
通讯作者Han, Dali; Yang, Cai-Guang; Xu, Meng Michelle
作者单位1.Tsinghua Univ, THU PKU Ctr Life Sci, Sch Med, Inst Immunol,Dept Basic Med Sci,Beijing Key Lab I, Beijing 100084, Peoples R China
2.Chinese Acad Sci, Beijing Inst Genom, Key Lab Genom & Precis Med, Beijing 100101, Peoples R China
3.Univ Chinese Acad Sci, Coll Future Technol, Sino Danish Coll, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
7.Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Sch Life Sci, Beijing 100084, Peoples R China
8.Peking Univ, Coll Engn, Dept Biomed Engn, State Key Lab Nat & Biomimet Drugs,Inst Mol Med, Beijing 100871, Peoples R China
9.Univ Chicago, Dept Chem, Chicago, IL 60637 USA
10.Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA
推荐引用方式
GB/T 7714		 Liu, Yi,Liang, Guanghao,Xu, Hongjiao,et al. Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance[J]. CELL METABOLISM,2021,33(6):1221-+.
APA Liu, Yi.,Liang, Guanghao.,Xu, Hongjiao.,Dong, Wenxin.,Dong, Ze.,...&Xu, Meng Michelle.(2021).Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance.CELL METABOLISM,33(6),1221-+.
MLA Liu, Yi,et al."Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance".CELL METABOLISM 33.6(2021):1221-+.

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来源：上海药物研究所

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