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

27 Citations (Scopus)

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

Fingerprint

Metabolism
Amino Acids
Serine
Transcriptional Activation
Cell proliferation
Histone Code
Genes
Histone Demethylases
Cell Proliferation
Gene Amplification
Biosynthesis
Transcription
Histones
Glycine
Lysine
Neoplasms
Carcinogenesis
Chemical activation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism. / Zhao, Erhu; Ding, Jane; Xia, Yingfeng; Liu, Mengling; Ye, Bingwei; Choi, Jeong Hyeon; Yan, Chunhong; Dong, Zheng; Huang, Shuang; Zha, Yunhong; Yang, Liqun; Cui, Hongjuan; Ding, Han Fei.

In: Cell Reports, Vol. 14, No. 3, 26.01.2016, p. 506-519.

Research output: Contribution to journalArticle

Zhao, E, Ding, J, Xia, Y, Liu, M, Ye, B, Choi, JH, Yan, C, Dong, Z, Huang, S, Zha, Y, Yang, L, Cui, H & Ding, HF 2016, 'KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism', Cell Reports, vol. 14, no. 3, pp. 506-519. https://doi.org/10.1016/j.celrep.2015.12.053
Zhao, Erhu ; Ding, Jane ; Xia, Yingfeng ; Liu, Mengling ; Ye, Bingwei ; Choi, Jeong Hyeon ; Yan, Chunhong ; Dong, Zheng ; Huang, Shuang ; Zha, Yunhong ; Yang, Liqun ; Cui, Hongjuan ; Ding, Han Fei. / KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism. In: Cell Reports. 2016 ; Vol. 14, No. 3. pp. 506-519.
@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}",
year = "2016",
month = "1",
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",

}

TY - JOUR

T1 - KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism

AU - Zhao, Erhu

AU - Ding, Jane

AU - Xia, Yingfeng

AU - Liu, Mengling

AU - Ye, Bingwei

AU - Choi, Jeong Hyeon

AU - Yan, Chunhong

AU - Dong, Zheng

AU - Huang, Shuang

AU - Zha, Yunhong

AU - Yang, Liqun

AU - Cui, Hongjuan

AU - Ding, Han Fei

PY - 2016/1/26

Y1 - 2016/1/26

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84953327405&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84953327405&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2015.12.053

DO - 10.1016/j.celrep.2015.12.053

M3 - Article

C2 - 26774480

AN - SCOPUS:84953327405

VL - 14

SP - 506

EP - 519

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 3

ER -