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

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

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63 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3016-3027
Number of pages	12
Journal	Cell Reports
Volume	16
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2016.08.018
Publication status	Published - Sept 13 2016
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.celrep.2016.08.018

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

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.",

author = "Wang, {Ling Yu} and Hung, {Chiu Lien} and Chen, {Yun Ru} and Yang, {Joy C.} and Junjian Wang and Mel Campbell and Yoshihiro Izumiya and Chen, {Hong Wu} and Wang, {Wen Ching} and Ann, {David K.} and Kung, {Hsing Jien}",

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doi = "10.1016/j.celrep.2016.08.018",

language = "English",

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T1 - KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis

AU - Wang, Ling Yu

AU - Hung, Chiu Lien

AU - Chen, Yun Ru

AU - Yang, Joy C.

AU - Wang, Junjian

AU - Campbell, Mel

AU - Izumiya, Yoshihiro

AU - Chen, Hong Wu

AU - Wang, Wen Ching

AU - Ann, David K.

AU - Kung, Hsing Jien

PY - 2016/9/13

Y1 - 2016/9/13

N2 - 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.

AB - 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.

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

Abstract

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