title: JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism.
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.
authors.affiliation: Institute of Molecular and Cellular Biology and Department of Life Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan.
authors.forename: Hung-Jung
authors.initials: HJ
authors.lastname: Wang
authors.forename: Ya-Ju
authors.initials: YJ
authors.lastname: Hsieh
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Cheng
authors.forename: Chun-Pu
authors.initials: CP
authors.lastname: Lin
authors.forename: Yu-shan
authors.initials: YS
authors.lastname: Lin
authors.forename: So-Fang
authors.initials: SF
authors.lastname: Yang
authors.forename: Chung-Ching
authors.initials: CC
authors.lastname: Chen
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Izumiya
authors.forename: Jau-Song
authors.initials: JS
authors.lastname: Yu
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.forename: Wen-Ching
authors.initials: WC
authors.lastname: Wang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000495:Allosteric Site; D001943:Breast Neoplasms / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D057809:HEK293 Cells; D006367:HeLa Cells; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000378:metabolism; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D013963:Thyroid Hormones / Q000378:metabolism*; D015533:Transcriptional Activation; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D005947:Glucose; D056466:Histone Demethylases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid; D008565:Membrane Proteins; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C497442:HIF1A protein, human; C550342:KDM8 protein, human
keywords: Warburg effect; aerobic glycolysis; breast cancer; cancer metabolism