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

Research output: Contribution to journalArticle

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)506-519
Number of pages14
JournalCell Reports
Volume14
Issue number3
DOIs
StatePublished - Jan 26 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Zhao, E., Ding, J., Xia, Y., Liu, M., Ye, B., Choi, J. H., Yan, C., Dong, Z., Huang, S., Zha, Y., Yang, L., Cui, H., & Ding, H. F. (2016). KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism. Cell Reports, 14(3), 506-519. https://doi.org/10.1016/j.celrep.2015.12.053