Format

Send to

Choose Destination
Cell Rep. 2016 Sep 13;16(11):3016-3027. doi: 10.1016/j.celrep.2016.08.018.

KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis.

Author information

1
Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA 95817, USA.
2
Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA 95817, USA; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 35053, Taiwan.
3
Department of Diabetes Complications and Metabolism, City of Hope, Duarte, CA 91010, USA.
4
Department of Urology, University of California, Davis, Sacramento, CA 95817, USA.
5
Department of Dermatology, University of California, Davis, Sacramento, CA 95817, USA.
6
Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA 95817, USA; Department of Dermatology, University of California, Davis, Sacramento, CA 95817, USA.
7
Department of Life Sciences, National Tsinghua University, Hsinchu 30013, Taiwan.
8
Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA 95817, USA; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 35053, Taiwan. Electronic address: hkung@nhri.org.tw.

Abstract

The histone lysine demethylase KDM4A/JMJD2A has been implicated in prostate carcinogenesis through its role in transcriptional regulation. Here, we describe KDM4A as a E2F1 coactivator and demonstrate a functional role for the E2F1-KDM4A complex in the control of tumor metabolism. KDM4A associates with E2F1 on target gene promoters and enhances E2F1 chromatin binding and transcriptional activity, thereby modulating the transcriptional profile essential for cancer cell proliferation and survival. The pyruvate dehydrogenase kinases (PDKs) PDK1 and PDK3 are direct targets of KDM4A and E2F1 and modulate the switch between glycolytic metabolism and mitochondrial oxidation. Downregulation of KDM4A leads to elevated activity of pyruvate dehydrogenase and mitochondrial oxidation, resulting in excessive accumulation of reactive oxygen species. The altered metabolic phenotypes can be partially rescued by ectopic expression of PDK1 and PDK3, indicating a KDM4A-dependent tumor metabolic regulation via PDK. Our results suggest that KDM4A is a key regulator of tumor metabolism and a potential therapeutic target for prostate cancer.

PMID:
27626669
PMCID:
PMC5024724
DOI:
10.1016/j.celrep.2016.08.018
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center