title: ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65.
abstract: The NF-κB is found in almost all animal cell types and is involved in a myriad of cellular responses. Aberrant expression of NF-κB has been linked to cancer, inflammatory diseases and improper development. Little is known about transcriptional regulation of the NF-κB family member gene RelA/p65. Sp1 plays a key role in the expression of the RelA/p65 gene. ZBTB2 represses transcription of the gene by inhibiting Sp1 binding to a Sp1-binding GC-box in the RelA/p65 proximal promoter (bp, -31 to -21). Moreover, recent studies revealed that RelA/p65 directly binds to the peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α) to decrease transcriptional activation of the PGC1α target gene PDK4, whose gene product inhibits pyruvate dehydrogenase (PDH), a key regulator of TCA cycle flux. Accordingly, we observed that RelA/p65 repression by ZBTB2 indirectly results in increased PDK4 expression, which inhibits PDH. Consequently, in cells with ectopic ZBTB2, the concentrations of pyruvate and lactate were higher than those in normal cells, indicating changes in glucose metabolism flux favoring glycolysis over the TCA cycle. Knockdown of ZBTB2 in mouse xenografts decreased tumor growth. ZBTB2 may increase cell proliferation by reprogramming glucose metabolic pathways to favor glycolysis by upregulating PDK4 expression via repression of RelA/p65 expression.
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Dong-In
authors.initials: DI
authors.lastname: Koh
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Bu-Nam
authors.initials: BN
authors.lastname: Jeon
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Deok-yoon
authors.initials: DY
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Kyung-Sup
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Kunhong
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea mwhur2@yuhs.ac.
authors.forename: Man-Wook
authors.initials: MW
authors.lastname: Hur
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000502:physiology*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; C000631432:PDK4 protein, human; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D051996:Transcription Factor RelA; C544396:ZBTB2 protein, human; D017346:Protein Serine-Threonine Kinases