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

Ling-Yu Wang; Chiu-Lien Hung; Yun-Ru Chen; Joy C Yang; Junjian Wang; Mel Campbell; Yoshihiro Izumiya; Hong-Wu Chen; Wen-Ching Wang; David K Ann; Hsing-Jien Kung

doi:10.1016/j.celrep.2016.08.018

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

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

Authors

Affiliations

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.

MeSH terms

Animals
Base Sequence
Cell Line, Tumor
Cell Proliferation
Chromatin / metabolism
E2F1 Transcription Factor / metabolism*
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Glycolysis*
Humans
Jumonji Domain-Containing Histone Demethylases / metabolism*
Male
Mice, Nude
Mitochondria / metabolism*
Oxidation-Reduction
Phenotype
Prostatic Neoplasms / genetics
Protein Binding
Protein Serine-Threonine Kinases / metabolism*
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Transcription, Genetic

Substances

Chromatin
E2F1 Transcription Factor
E2F1 protein, human
PDK1 protein, human
PDK3 protein, human
Pdk1 protein, mouse
Pdk3 protein, mouse
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Jumonji Domain-Containing Histone Demethylases
KDM4A protein, human
Protein Serine-Threonine Kinases

Abstract

MeSH terms

Substances

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