JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism

Hung Jung Wang, Ya Ju Hsieh, Wen Chi Cheng, Chun Pu Lin, Yu Shan Lin, So Fang Yang, Chung Ching Chen, Yoshihiro Izumiya, Jau Song Yu, Hsing Jien Kung, Wen Ching Wang

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

JMJD5, a Jumonji C domain-containing dioxygenase, is important for embryonic development and cancer growth. Here, we show that JMJD5 is up-regulated by hypoxia and is crucial for hypoxiainduced cell proliferation. JMJD5 interacts directly with pyruvate kinase muscle isozyme (PKM)2 to modulate metabolic flux in cancer cells. The JMJD5-PKM2 interaction resides at the intersubunit interface region of PKM2, which hinders PKM2 tetramerization and blocks pyruvate kinase activity. This interaction also influences translocation of PKM2 into the nucleus and promotes hypoxiainducible factor (HIF)-1α-mediated transactivation. JMJD5 knockdown inhibits the transcription of the PKM2-HIF-1α target genes involved in glucose metabolism, resulting in a reduction of glucose uptake and lactate secretion in cancer cells. JMJD5, along with PKM2 and HIF-1α, is recruited to the hypoxia response element site in the lactate dehydrogenase A and PKM2 loci and mediates the recruitment of the latter two proteins. Our data uncover a mechanism whereby PKM2 can be regulated by factor-binding- induced homo/heterooligomeric restructuring, paving the way to cell metabolic reprogram.

Original languageEnglish
Pages (from-to)279-284
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number1
DOIs
Publication statusPublished - Jan 16 2014
Externally publishedYes

Keywords

  • Aerobic glycolysis
  • Breast cancer
  • Cancer metabolism
  • Warburg effect

ASJC Scopus subject areas

  • General

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  • Cite this

    Wang, H. J., Hsieh, Y. J., Cheng, W. C., Lin, C. P., Lin, Y. S., Yang, S. F., Chen, C. C., Izumiya, Y., Yu, J. S., Kung, H. J., & Wang, W. C. (2014). JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism. Proceedings of the National Academy of Sciences of the United States of America, 111(1), 279-284. https://doi.org/10.1073/pnas.1311249111