title: KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism.
abstract: The histone lysine demethylase KDM4C is often overexpressed in cancers primarily through gene amplification. The molecular mechanisms of KDM4C action in tumorigenesis are not well defined. Here, we report that KDM4C transcriptionally activates amino acid biosynthesis and transport, leading to a significant increase in intracellular amino acid levels. Examination of the serine-glycine synthesis pathway reveals that KDM4C epigenetically activates the pathway genes under steady-state and serine deprivation conditions by removing the repressive histone modification H3 lysine 9 (H3K9) trimethylation. This action of KDM4C requires ATF4, a transcriptional master regulator of amino acid metabolism and stress responses. KDM4C activates ATF4 transcription and interacts with ATF4 to target serine pathway genes for transcriptional activation. We further present evidence for KDM4C in transcriptional coordination of amino acid metabolism and cell proliferation. These findings suggest a molecular mechanism linking KDM4C-mediated H3K9 demethylation and ATF4-mediated transactivation in reprogramming amino acid metabolism for cancer cell proliferation.
authors.affiliation: State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400715, China; Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Erhu
authors.initials: E
authors.lastname: Zhao
authors.affiliation: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Ding
authors.affiliation: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Insititute of Translational Neuroscience and Department of Neurology, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang 443000, China.
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Insititute of Translational Neuroscience and Department of Neurology, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang 443000, China.
authors.forename: Mengling
authors.initials: M
authors.lastname: Liu
authors.affiliation: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Bingwei
authors.initials: B
authors.lastname: Ye
authors.affiliation: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Department of Biostatistics and Epidemiology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Cell Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32611, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.affiliation: Insititute of Translational Neuroscience and Department of Neurology, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang 443000, China.
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Zha
authors.affiliation: State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400715, China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400715, China. Electronic address: hcui@swu.edu.cn.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Cui
authors.affiliation: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: hding@gru.edu.
authors.forename: Han-Fei
authors.initials: HF
authors.lastname: Ding
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000032:analysis / Q000096:biosynthesis*; D002455:Cell Division; D045744:Cell Line, Tumor; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D050543:Phosphoglycerate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C497109:ATF4 protein, human; D000596:Amino Acids; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D006657:Histones; D018398:Homeodomain Proteins; C522807:Hoxc9 protein, human; C413655:KDM4C protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051701:Activating Transcription Factor 4; D050543:Phosphoglycerate Dehydrogenase; D056484:Jumonji Domain-Containing Histone Demethylases