@article{f6298baeeee94f818ea18bddd11ac06c,
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.",
author = "Erhu Zhao and Jane Ding and Yingfeng Xia and Mengling Liu and Bingwei Ye and Choi, {Jeong Hyeon} and Chunhong Yan and Zheng Dong and Shuang Huang and Yunhong Zha and Liqun Yang and Hongjuan Cui and Ding, {Han Fei}",
note = "Funding Information: We thank Dr. Nabieh Ayoub of the Israel Institute of Technology for providing pEGFP-KDM4C-wt and pEGFP-KDM4C-S198M, and Drs. LesleyAnn Hawthorn, Sam Chang, and Eiko Kitamura of the Georgia Regents University Cancer Center Genomics Core for assistance in microarray gene expression profiling. The work was supported by a grant from the National Basic Research Program of China (2012CB114603 to H.C.), grants from the NIH (R01 CA190429 to H.-F.D.) and US Department of Defense (W81XWH-12-1-0613 to H.-F.D.), and a grant from the National Natural Science Foundation of China (81201981 to Y.Z.). Funding Information: We thank Dr. Nabieh Ayoub of the Israel Institute of Technology for providing pEGFP-KDM4C-wt and pEGFP-KDM4C-S198M, and Drs. LesleyAnn Hawthorn, Sam Chang, and Eiko Kitamura of the Georgia Regents University Cancer Center Genomics Core for assistance in microarray gene expression profiling. The work was supported by a grant from the National Basic Research Program of China ( 2012CB114603 to H.C.), grants from the NIH ( R01 CA190429 to H.-F.D.) and US Department of Defense ( W81XWH-12-1-0613 to H.-F.D.), and a grant from the National Natural Science Foundation of China ( 81201981 to Y.Z.). Publisher Copyright: {\textcopyright} 2016 The Authors.",
year = "2016",
month = jan,
day = "26",
doi = "10.1016/j.celrep.2015.12.053",
language = "English (US)",
volume = "14",
pages = "506--519",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}
