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PMID: 29249359 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling.

Cell ·Vol. 172 ·No. 1-2 ·2018-00-11 ·Pages 90-105.e23

Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y, Deng X, Wang Y, Weng X, Hu C, Yu M, Skibbe J, Dai Q, Zou D, Wu T, Yu K, Weng H, Huang H, Ferchen K, Qin X, Zhang B, Qi J, Sasaki AT, Plas DR, Bradner JE, Wei M, Marcucci G, Jiang X, Mulloy JC, Jin J, He C, Chen J

Abstract

R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N6-methyladenosine (m6A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2 mutant cancers contributes to cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m6A/MYC/CEBPA signaling.

Keywords
CEBPA FTO IDH mutation MYC N(6)-methyladenosine (m(6)A) R-2HG S-2HG glioma leukemia
MeSH Terms
Adenosine/analogs & derivatives,metabolism Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism Animals Antineoplastic Agents/pharmacology,therapeutic use Brain Neoplasms/drug therapy CCAAT-Enhancer-Binding Proteins/metabolism Cell Line, Tumor Glioma/drug therapy Glutarates/pharmacology,therapeutic use HEK293 Cells Humans Jurkat Cells Leukemia/drug therapy Mice Proto-Oncogene Proteins c-myc/metabolism RNA Processing, Post-Transcriptional Signal Transduction/drug effects
Chemicals
Antineoplastic Agents CCAAT-Enhancer-Binding Proteins CEBPA protein, mouse Glutarates Proto-Oncogene Proteins c-myc alpha-hydroxyglutarate N-methyladenosine FTO protein, mouse Alpha-Ketoglutarate-Dependent Dioxygenase FTO Adenosine
Authors & Affiliations
32 authors, click to expand affiliations / ORCID
Su Rui
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.
Dong Lei
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.
Li Chenying
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; Key Laboratory of Hematopoietic Malignancies, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China.
Nachtergaele Sigrid
Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
Wunderlich Mark
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Qing Ying
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.
Deng Xiaolan
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.
Wang Yungui
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; Key Laboratory of Hematopoietic Malignancies, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China.
Weng Xiaocheng
Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA; College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, Wuhan University, Hubei, Wuhan 430072, China.
Hu Chao
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; Key Laboratory of Hematopoietic Malignancies, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China.
Yu Mengxia
Key Laboratory of Hematopoietic Malignancies, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China.
Skibbe Jennifer
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.
Dai Qing
Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
Zou Dongling
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; Depart of Gynecologic Oncology, Chongqing Cancer Institute and Hospital and Cancer Center, Chongqing 400030, China.
Wu Tong
Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
Yu Kangkang
Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
Weng Hengyou
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.
Huang Huilin
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.
Ferchen Kyle
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.
Qin Xi
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.
Zhang Bin
Gehr Family Center for Leukemia Research, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA.
Qi Jun
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Sasaki Atsuo T
Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Plas David R
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.
Bradner James E
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Wei Minjie
School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.
Marcucci Guido
Gehr Family Center for Leukemia Research, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA.
Jiang Xi
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.
Mulloy James C
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Jin Jie
Key Laboratory of Hematopoietic Malignancies, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China. Electronic address: jiej0503@163.com.
He Chuan
Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.
Chen Jianjun
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; Gehr Family Center for Leukemia Research, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA. Electronic address: jianchen@coh.org.
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2017.11.031
Email
jiej0503@163.com
chuanhe@uchicago.edu
jianchen@coh.org
Published
2018-00-11
Epub
2017-00-14
Pages
90-105.e23
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC5766423
Subset
IM
Grants
NHGRI NIH HHS · RM1 HG008935 · United States
NCI NIH HHS · R50 CA211404 · United States
NCI NIH HHS · R01 CA182528 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · R01 GM071440 · United States
NCI NIH HHS · R01 CA214965 · United States
NINDS NIH HHS · R01 NS089815 · United States
NCI NIH HHS · R01 CA168815 · United States
NINDS NIH HHS · R21 NS100077 · United States
NCI NIH HHS · R01 CA178454 · United States
NCI NIH HHS · R01 CA211614 · United States
Corrections
CommentIn
PMID: 29269348
External Links
PubMed source DOI: 10.1016/j.cell.2017.11.031 PMC Full Text View journal details
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