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 hypoxia-induced 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 hypoxia-inducible 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.
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Authors | 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 |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 111
Issue 1
Pg. 279-84
(Jan 07 2014)
ISSN: 1091-6490 [Electronic] United States |
PMID | 24344305
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Carrier Proteins
- HIF1A protein, human
- Hypoxia-Inducible Factor 1, alpha Subunit
- Isoenzymes
- Membrane Proteins
- Thyroid Hormones
- thyroid hormone-binding proteins
- Lactic Acid
- L-Lactate Dehydrogenase
- Lactate Dehydrogenase 5
- Histone Demethylases
- KDM8 protein, human
- Glucose
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Topics |
- Active Transport, Cell Nucleus
- Allosteric Site
- Breast Neoplasms
(metabolism)
- Carrier Proteins
(metabolism)
- Cell Line, Tumor
- Cell Nucleus
(metabolism)
- Cell Proliferation
- Female
- Gene Expression Regulation, Neoplastic
- Glucose
(metabolism)
- Glycolysis
- HEK293 Cells
- HeLa Cells
- Histone Demethylases
(metabolism)
- Humans
- Hypoxia
- Hypoxia-Inducible Factor 1, alpha Subunit
(metabolism)
- Isoenzymes
(metabolism)
- L-Lactate Dehydrogenase
(metabolism)
- Lactate Dehydrogenase 5
- Lactic Acid
(metabolism)
- MCF-7 Cells
- Membrane Proteins
(metabolism)
- Neoplasms
(metabolism)
- Protein Binding
- Protein Structure, Quaternary
- Thyroid Hormones
(metabolism)
- Transcriptional Activation
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