KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism

Erhu Zhao; Jane Ding; Yingfeng Xia; Mengling Liu; Bingwei Ye; Jeong-Hyeon Choi; Chunhong Yan; Zheng Dong; Shuang Huang; Yunhong Zha; Liqun Yang; Hongjuan Cui; Han-Fei Ding

doi:10.1016/j.celrep.2015.12.053

KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism

Cell Rep. 2016 Jan 26;14(3):506-519. doi: 10.1016/j.celrep.2015.12.053. Epub 2016 Jan 7.

Authors

Erhu Zhao¹, Jane Ding², Yingfeng Xia³, Mengling Liu³, Bingwei Ye², Jeong-Hyeon Choi⁴, Chunhong Yan⁵, Zheng Dong⁶, Shuang Huang⁷, Yunhong Zha⁸, Liqun Yang⁹, Hongjuan Cui¹⁰, Han-Fei Ding¹¹

Affiliations

¹ 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.
² Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
³ 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.
⁴ 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.
⁵ 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.
⁶ Department of Cell Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
⁷ Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32611, USA.
⁸ Insititute of Translational Neuroscience and Department of Neurology, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang 443000, China.
⁹ State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400715, China.
¹⁰ State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400715, China. Electronic address: [email protected].
¹¹ 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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Activating Transcription Factor 4 / genetics
Activating Transcription Factor 4 / metabolism*
Amino Acids / analysis
Amino Acids / biosynthesis*
Cell Division
Cell Line, Tumor
Forkhead Box Protein M1
Forkhead Transcription Factors / metabolism
Gas Chromatography-Mass Spectrometry
HeLa Cells
Histones / metabolism
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
Jumonji Domain-Containing Histone Demethylases / genetics
Jumonji Domain-Containing Histone Demethylases / metabolism*
Methylation
Phosphoglycerate Dehydrogenase / genetics
Phosphoglycerate Dehydrogenase / metabolism
Promoter Regions, Genetic
RNA Interference
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
Transcription, Genetic

Substances

ATF4 protein, human
Amino Acids
FOXM1 protein, human
Forkhead Box Protein M1
Forkhead Transcription Factors
Histones
Homeodomain Proteins
Hoxc9 protein, human
KDM4C protein, human
RNA, Messenger
RNA, Small Interfering
Activating Transcription Factor 4
Phosphoglycerate Dehydrogenase
Jumonji Domain-Containing Histone Demethylases

Grants and funding

R01 CA190429/CA/NCI NIH HHS/United States