KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis.
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.
Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA 95817, USA.
Ling-Yu
LY
Wang
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.
Chiu-Lien
CL
Hung
Department of Diabetes Complications and Metabolism, City of Hope, Duarte, CA 91010, USA.
Yun-Ru
YR
Chen
Department of Urology, University of California, Davis, Sacramento, CA 95817, USA.
Joy C
JC
Yang
Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA 95817, USA.
Junjian
J
Wang
Department of Dermatology, University of California, Davis, Sacramento, CA 95817, USA.
Mel
M
Campbell
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.
Yoshihiro
Y
Izumiya
Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA 95817, USA.
Hong-Wu
HW
Chen
Department of Life Sciences, National Tsinghua University, Hsinchu 30013, Taiwan.
Wen-Ching
WC
Wang
Department of Diabetes Complications and Metabolism, City of Hope, Duarte, CA 91010, USA.
David K
DK
Ann
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.
Hsing-Jien
HJ
Kung
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006019:Glycolysis; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008297:Male; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014158:Transcription, Genetic
D002843:Chromatin; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C000631429:PDK1 protein, human; C000631431:PDK3 protein, human; C000631433:Pdk1 protein, mouse; C000631437:Pdk3 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; D017346:Protein Serine-Threonine Kinases