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.

journal_name

Cell Rep

journal_title

Cell reports

authors

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

doi

10.1016/j.celrep.2015.12.053

subject

Has Abstract

pub_date

2016-01-26 00:00:00

pages

506-519

issue

3

issn

2211-1247

pii

S2211-1247(15)01494-1

journal_volume

14

pub_type

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