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JMJD5 Regulates PKM2 Nuclear Translocation and Reprograms HIF-1Α–Mediated Glucose Metabolism

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JMJD5 Regulates PKM2 Nuclear Translocation and Reprograms HIF-1Α–Mediated Glucose Metabolism JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α–mediated glucose metabolism Hung-Jung Wanga,b, Ya-Ju Hsiehc, Wen-Chi Chenga, Chun-Pu Lina, Yu-shan Lina, So-Fang Yanga, Chung-Ching Chena, Yoshihiro Izumiyad, Jau-Song Yuc, Hsing-Jien Kungb,d,1, and Wen-Ching Wanga,e,1 aInstitute of Molecular and Cellular Biology and Department of Life Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan; bNational Health Research Institutes, Miaoli 35053, Taiwan; cProteomics Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Tao-Yuan 33302, Taiwan; dDepartment of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, University of California Davis Cancer Center, Sacramento, CA 95817; and eCenter of Biomedical Science and Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan Edited* by Shu Chien, University of California, San Diego, La Jolla, CA, and approved November 19, 2013 (received for review June 13, 2013) JMJD5, a Jumonji C domain-containing dioxygenase, is important (FBP), amino acid serine (7), and SAICAR (succinylaminoimi- for embryonic development and cancer growth. Here, we show dazolecarboxamide ribose-5′-phosphate), a metabolite of the de that JMJD5 is up-regulated by hypoxia and is crucial for hypoxia- novo purine nucleotide synthesis pathway (8). On the other hand, induced cell proliferation. JMJD5 interacts directly with pyruvate various stimuli including growth factors are known to negatively kinase muscle isozyme (PKM)2 to modulate metabolic flux in can- affect the pyruvate kinase activity of PKM2, thereby diverting the cer cells. The JMJD5-PKM2 interaction resides at the intersubunit metabolic flow to the anabolic process. This was carried out interface region of PKM2, which hinders PKM2 tetramerization principally by posttranslational modifications: Y105 phosphory- and blocks pyruvate kinase activity. This interaction also influen- lation by FGFR1 (9, 10), K305 acetylation in the presence of ces translocation of PKM2 into the nucleus and promotes hypoxia- high-glucose concentrations (11), and C358 oxidation upon ele- inducible factor (HIF)-1α–mediated transactivation. JMJD5 knock- vated reactive oxygen species levels (12). However, another way of modulating cytosolic PKM2 activity is its translocation into down inhibits the transcription of the PKM2–HIF-1α target genes nucleus, where it serves as a transcriptional coactivator (13, 14) involved in glucose metabolism, resulting in a reduction of glucose or as a phosphotransferase (15) to modulate transcriptional pro- uptake and lactate secretion in cancer cells. JMJD5, along with gram. Thus, PKM2 is found to function as a coactivator for Oct4, α CELL BIOLOGY PKM2 and HIF-1 , is recruited to the hypoxia response element β-catenin, Stat3, and hypoxia-inducible factor (HIF)-1α (13–16). PKM2 site in the lactate dehydrogenase A and loci and mediates PKM2 interacts with Oct4 to increase Oct4-mediated transacti- the recruitment of the latter two proteins. Our data uncover vation potential (16). Nuclear PKM2 associates with phosphory- a mechanism whereby PKM2 can be regulated by factor-binding– lated β-catenin upon EGFR activation to promote cyclin D1 (13). induced homo/heterooligomeric restructuring, paving the way to PKM2 binds to and phosphorylates Stat3 and histone H3 (17), cell metabolic reprogram. activating gene transcription and tumorigenesis. Thus, both cyto- solic and nuclear PKM2 contribute to altered metabolism and Warburg effect | aerobic glycolysis | breast cancer | cancer metabolism proliferation in cancer. The mechanisms associated with PKM2 translocation are multiple, including phosphorylation by ERK1 at S37 (18) and hydroxylation by PHD3 at P403 and P408 (14). MJD5 is a Jumonji C domain-containing dioxygenase shown α Jto be involved in lysine demethylation (1–3) and hydroxylation The latter allows PKM2 to bind HIF-1 and hypoxia response functions (4). Although the exact cellular substrates and func- elements (HREs) to regulate metabolic gene transcription and promote tumorigenesis under hypoxic conditions. tions of JMJD5 remain unclear, JMJD5 was shown to positively – In this investigation, we describe a role of JMJD5 as a major regulate cyclin A1 but negatively regulate p53 and p21 (1 3). regulator of PKM2. We describe a mechanism whereby PKM2 is Knockdown of JMJD5 in Michigan Cancer Foundation (MCF)-7 − − cells inhibits cell proliferation (1), and JMJD5 / embryos showed Significance severe growth retardation, resulting in embryonic lethality at the midgestation stage (3). These data, together with its general over- expression in tumor tissues, implicate a role of JMJD5 in carci- Cancer cells favor high rates of aerobic glycolysis, or the War- nogenesis. In this paper, we define a role of JMJD5 in regulating burg effect, which is mediated by a key molecule, pyruvate kinase muscle isozyme (PKM)2. PKM2 functions both as a cy- tumor metabolism under normoxic and hypoxic conditions through tosolic enzyme and a nuclear factor in tumor cells. This report its interaction with pyruvate kinase muscle isozyme (PKM)2. ’ One of the hallmarks of cancer cells is their altered metabo- shows that PKM2 s nuclear translocation is regulated by lism, referred to as aerobic glycolysis, or the Warburg effect (5). Jumonji C domain-containing dioxygenase (JMJD)5 via direct This generally involves an increased uptake of glucose, use of physical binding. JMJD5 hinders the PKM2 tetrameric assembly and facilitates PKM2’s nuclear translocation. Together, they intracellular glucose to pyruvate via glycolysis, and the conver- α sion into lactate in the presence of sufficient oxygen. Along this modulate hypoxia-inducible factor 1 -mediated transcriptional metabolic flux, PKM1 or its spliced variant, PKM2, which de- reprogramming of metabolic genes. These results reveal a ’ phosphorylates phosphoenolpyruvate (PEP) into pyruvate, the last mechanism whereby PKM2 s activity can be modulated by a step of glycolysis, is an important signal integrator whose activities dioxygenase/demethylase. determine the cytosolic level of pyruvate, thereby affecting sub- sequent metabolic flow to lactate, tricarboxylic acid cycle or bio- Author contributions: H.-J.W., H.-J.K., and W.-C.W. designed research; H.-J.W., Y.-J.H., W.-C.C., C.-P.L., Y.-s.L., S.-F.Y., and C.-C.C. performed research; Y.-J.H., Y.I., J.-S.Y., and H.-J.K. synthetic pathway (6). Enzymatically, PKM2, an embryonic isoform contributed new reagents/analytic tools; H.-J.W., Y.-J.H., W.-C.C., C.-P.L., Y.-s.L., S.-F.Y., found abundantly in tumor cells, is less active than PKM1, which C.-C.C., J.-S.Y., H.-J.K., and W.-C.W. analyzed data; and H.-J.W., H.-J.K., and W.-C.W. allows the accumulation of glycolytic intermediates and diversion wrote the paper. into biosynthetic pathways, demanded by rapid-proliferating cells. The authors declare no conflict of interest. As a pivotal regulator of tumor metabolism, PKM2’s activity is *This Direct Submission article had a prearranged editor. further modulated by allosteric regulation via cofactor bindings, 1To whom correspondence may be addressed. E-mail: [email protected] or wcwang@ oligomerization, and posttranslational modification to cope with life.nthu.edu.tw. the ever-changing environment for tumor growth. For example, cy- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tosolic PKM2 is allosterically activated by fructose 1,6-bisphosphate 1073/pnas.1311249111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1311249111 PNAS | January 7, 2014 | vol. 111 | no. 1 | 279–284 Downloaded by guest on September 27, 2021 translocated into the nucleus to regulate cancer metabolism. We found that the JMJD5-knockdown cells significantly reduced We show that JMJD5 is up-regulated and contributes to hyp- the glucose uptake (Fig. 1D) and lactate secretion (Fig. 1E) oxia-induced cell proliferation. We demonstrate that JMJD5 compared with the control cells either under normoxia or hyp- interacts with PKM2, alters the monomer:dimer:tetramer equi- oxia. We then tested the expression profiles of genes involved librium, and blocks pyruvate kinase activity. Furthermore, JMJD5 in the Warburg effect using real-time quantitative (qRT)-PCR accelerates the translocation of PKM2 into the nucleus and analysis; they include the glucose transporter (GLUT1), hexo- enhances the binding of HIF-1α to the target genes, paving the kinase II (HK2), enolase 1 (ENO1), PKM2, lactate dehydro- way to cancer-specific metabolism in response to low-oxygen genase A (LDHA), lactate transporter MCT4 (MCT4), and challenge. pyruvate dehydrogenase lipoamide kinase isozyme 1 (PDK1) (Fig. 1C). The control LKO cells exhibited a relatively higher Results level of expression of all these genes than shJMJD5 cells cultured JMJD5 Knockdown Reduces Cell Growth and Glycolytic Genes in MCF- under normoxia, in which statistical significance was seen for 7 Breast Cancer Cells Under Normoxia and Hypoxia. JMJD5 is highly HK2 and PKM2 (Fig. 1F). There was even a much higher ex- expressed in breast cancer cells and exerts a proliferative func- pression for all these genes in LKO than in shJMJD5 under low- GLUT1 tion (1). Given that cancer cells frequently suffer from in- oxygen condition; statistical significance was found for , ENO1, PKM2, LDHA, and PDK1. Of note, GLUT1, LDHA, and termittent hypoxia exposure, we sought to test the role of JMJD5 PDK1 are known to be responsible for increased glucose uptake in MCF-7 cells under both
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