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

研究成果: 雜誌貢獻文章

26 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)3016-3027
頁數12
期刊Cell Reports
16
發行號11
DOIs
出版狀態已發佈 - 九月 13 2016
對外發佈Yes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Wang, L. Y., Hung, C. L., Chen, Y. R., Yang, J. C., Wang, J., Campbell, M., Izumiya, Y., Chen, H. W., Wang, W. C., Ann, D. K., & Kung, H. J. (2016). KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis. Cell Reports, 16(11), 3016-3027. https://doi.org/10.1016/j.celrep.2016.08.018